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June 13, 2012
NIH HUMAN MICROBIOME PROJECT COMPLETES SEMINAL STUDY OF MICROBIAL DIVERSITY IN HEALTHY VOLUNTEERS

The NIH Common Fund’s Human Microbiome Project (HMP) has just published two seminal papers in the June 14, 2012 issue of Nature and a series of additional papers in several PLoS journals (click here  for more), the NIH announces on June 13, 2012.

These milestone studies are centered on the project’s ambitious and unparalleled examination and analysis of the microbiomes of a healthy cohort consisting of over 240 individuals. The resources and resulting analysis shed light onto the intricate details of the complete healthy human microbiome and pave the way for future studies in the field. The diversity both within and among body sites highlights an important and complex association between humans and associated microbes.

A comprehensive community resource

One of the two Nature papers from the June 14 issue examined a population of 242 healthy adults, each of whom were sampled at 15 (male) to 18 (female) body sites, with each person sampled on one to three  distinct occasions.

This unparalleled effort led to DNA sequencing of microbial eukaryotes, archaea, bacteria, and viruses (both mammalian and bacterial). Using standardized protocols and methods across the four sequencing centers, the consortium was able to generate 5,177 unique microbial taxonomic profiles (from 16S rRNA gene sequences) and over 3.5 Tbp of metagenomic sequence. Furthermore, their studies led to the assembly of hundreds of reference genomes  from the human microbiome.

These efforts have led to an expansive generation of genomic data and also extensive data related to functional proteins and site-specific metabolism. The targeted approach of assembling data in a site-specific manner allowed the researchers to assemble less abundant organisms that were common across the cohort. In addition to the microbial analyses, healthy cohort subjects also submitted blood samples so that human genome analysis and cell-line development can be implemented in future studies.

This foresight in the project’s planning unlocks an area of great potential for benefits to human health. Much of the data, other than protected health information, is publicly available via NCBI HMP project page and the HMP Data Analysis and Coordinating Center (DACC).      

Extensive analysis of the healthy human microbiome

After establishing standards for data generation, the HMP consortium continued on to conduct a comprehensive analysis of the largest human cohort and set of distinct, clinically relevant body habitats to date (five major habitats).

This is the first study to include metagenomic data (data that does not rely on culturing microbes) across body habitats from a cohort of this magnitude, in an attempt to describe the basics of overall host associated microbial life as well as the basics of microbial life for each host site examined.

 The research team found that there was strong site specialization both within and among subjects but that the diversity and abundance of each habitat’s signature microbes varied widely among the healthy subjects. Somewhat surprisingly based on the genetic sequence with large phylogenetic variations and general variation among the individual samples, there was remarkable functional stability.

In essence, the authors illustrate that while the compositions vary widely the functionality is similar, meaning that there are many ways to construct microbial communities to perform similar functions.

Through this analysis, the consortium was also able to make general characterizations about the human microbiome. One finding was a limited, but commonly detectable, number of pathogens, leading to speculation that a low abundance of potentially harmful microbes might in some cases be beneficial to the host.

Another interesting finding was patterns of alpha and beta diversity, where alpha diversity is defined as the diversity within a site and beta diversity is defined as that observed among subjects. For example, saliva was shown to have high alpha diversity (many different taxonomical units) but low beta diversity (very similar among the cohort). Human sites varied widely in alpha and beta diversity and future characterizations of the microbiome and its relation to human diseases will likely shed further light onto the importance of these variations in healthy and disease states.

A major finding from the analysis of the healthy cohort was a number of well-validated correlations of taxa (groups of organisms) and function with host phenotypes. Some of the greatest correlations observed were between ethnicity and microbiome composition across all body habitats and a positive correlation of vaginal pH to microbial diversity (higher pH having higher diversity).

Furthermore, there was an intriguing association of age with skin microbiome-associated metabolic pathways and oral microbiome composition, and a modest correlation between microbial composition and body mass index. Overall, many correlations were observed but as of now most of the data is not fully understood and requires future studies and examinations of additional factors including diet and host genetics.

A true team effort

The results presented in these papers highlight a remarkable level of collaboration among a large number of researchers. Interactions and collaborations among the two clinical centers and four sequencing centers were paramount for success.

 During the early stages of the program, data were being generated at an exponentially faster rate than analyses could be performed. To address these issues, the consortium formed the Data Analysis Working Group (DAWG), which consists of members from the genome centers and computational tools groups in addition to several experts not directly supported by the HMP. This was critical for the success of this large-scale and collaborative process. The partnerships and synergism from this teamwork will continue to fuel microbiome research.

The two landmark papers and the series of companion papers establish a foundation to catalyze and aid a myriad of studies ranging from basic to translational to clinical. For more information about the NIH Common Fund Human Microbiome Project please visit the Common Fund HMP and HMP Data Analysis and Coordinating Center (DACC) websites.



May 31, 2012

RESEARCHERS DISCOVER STRUCTURE OF OPIOID RECEPTORS

Opioid receptors are proteins found on the surface of cells in the nervous and digestive systems that bind opioid proteins, molecules that naturally occur in the body and play a role in regulating pain, pleasure, mood, addiction, and digestion.

 An array of legal and illegal drugs such as morphine, codeine, and heroin also bind to these receptors and control their activity, but usually with unwanted side effects such as hallucinations and addiction, which limits their clinical use. The development of selective therapeutics that control the activity of opioid receptors without these side effects holds great promise as pain relievers, anti-depressants, and anti-anxiety treatments.

The development of such agents could have a revolutionizing effect on the treatment of acute and chronic pain, several neuropsychiatric disorders, and addiction.

Dr. Raymond Stevens, partly funded by the NIH Common Fund’s Structural Biology program and the National Institute of General Medical Science’s Protein Structure Initiative, along with colleagues, has published the three-dimensional structures of two members of the human opioid receptor family- the kappa opioid receptor (KOR) and the nociceptin/orphanin FQ peptide receptor (NOP).

As reported in the May 17, 2012 issue of Nature, these structures reveal unprecedented detail about the shape of these receptors, which may allow researchers to design drugs that can interact with these receptors in specific ways to elicit only the desired effects. KOR is the only receptor that binds the active ingredient in the plant Salvia divinorum (also known as “Salvia” or “Magic Mint”), which has recently gained popularity as a recreational drug of abuse causing hallucinations and psychedelic experiences (see the National Institute of Drug Abuse InfoFacts: Salvia).

The part of the receptors where drugs and other molecules bind, called the binding pocket, is very large in both KOR and NOP. KOR and NOP differ in only a few specific places within the binding pocket, but these differences result in significant changes in the shape of the pocket, explaining why some molecules specifically bind to one receptor, but not the other.

In the same issue of Nature, Dr. Brian Kobilka and colleagues published the structures of the mu and delta opioid receptors; collectively, these four papers reveal the structures of the entire family of human opioid receptors. Drs. Stevens and Kobilka used sophisticated techniques, developed in part through previous Common Fund support, to create the protein crystals needed to reveal the underlying protein structure.

These studies provide a major clue in understanding the selectivity of opioid receptors, opening up new avenues of research into basic research about brain function and consciousness, as well as the development of clinically useful therapeutics.  
Read the university news release….

Read more about the Structural Biology Program…

Read more about the Joint Center for Innovative Membrane Protein Technologies (JCIMPT)-Complexes….

References:

Wu H, Wacker D, Katritch V, Mileni M, Han GW, Vardy E, Liu W, Thompson AA, Huang XP, Carroll FI, Mascarella SW, Westkaemper RB, Mosier PD, Roth BL, Cherezov V, Stevens RC. Structure of the human kappa opioid receptor in complex with JDTic. Nature, 2012 Mar 21 (online publication date); 485(7398): 327-32. PMID: 22437504.

Thompson AA, Liu W, Chun E, Katritch V, Wu H, Vardy E, Huang X-P, Trapella C, Guerrini R, Calo G, Roth BL, Cherezov V, Stevens RC. Structure of the nociceptin/orphanin FQ receptor in complex with a peptide mimetic. Nature, 2012 May 16; 485(7398):395-9. PMID: 22596163.

Manglik A, Kruse AC, Kobilka TS, Thian FS, Mathiesen JM, Sunahara RK, Pardo L, Weis WI, Kobilka BK, Granier S. Crystal structure of the mu-opioid receptor bound to a morphinan antagonist. Nature, 2012 Mar 21 (online publication date); 485(7398): 321-6. PMID: 22437502.

Granier S, Manglik A, Kruse AC, Kobilka TS, Thian FS, Weis WI, Kobilka B. Structure of the delta-opioid receptor bound to naltrindole. Nature, 2012 May 16; 485(7398): 400-4. PMID: 22596164.


February 16, 2012
COMMON FUND RESEARCHERS UNCOVER STRUCTURE OF IMPORTANT TARGET FOR DRUG DESIGN
Researchers supported by the NIH Common Fund and the National Institute of General Medical Sciences teamed up to characterize an important G Protein-coupled receptor (GPCR). GPCRs are a class of membrane proteins involved in an array of physiological functions and human diseases, including multiple sclerosis. Importantly, these receptor proteins are the target of approximately 40% of all medications currently on the market. Using technology developed in part through support from the Common Fund’s Structural Biology Program, the research teams of Drs. Raymond Stevens and Hugh Rosen at The Scripps Research Institute teamed up to examine the GPCR sphingosine 1-phosphate 1 (S1P1) bound to different activators and inhibitors developed through the Common Fund’s Molecular Libraries and Imaging Program. S1P1 receptors play critical roles in controlling multiple sclerosis and other diseases, making the discovery useful for advancing treatment options. Advances made in this study allowed the researchers to identify how molecules bind in different ways to the receptor and better understand at a detailed level how access to the binding pocket is gained. These advances pave the way for more targeted drug design that will yield highly effective therapeutics with fewer side effects than current treatments. These findings were published in the February 17, 2012 issue of the journal Science.

Read the NIH press release
Read more about the Molecular Libraries and Imaging program…
Read more about the Structural Biology program…

References:

Hanson MA, Roth CB, Jo E, Griffith MT, Scott FL, Reinhart G, Desale H, Clemons B, Cahalan SM, Schuerer SC, Sanna MG, Han GW, Kuhn P, Rosen H, Stevens RC. Crystal structure of lipid G protein-coupled receptor. Science, 2012 Feb 17; 335(6070): 851-5. PMID: 22344443.


December 15, 2011
BACK TO THE BASICS TO FIND A CURE FOR TUBERCULOSIS
It’s estimated that about one third of the world’s population is infected with Tuberculosis. Treatment of Tuberculosis usually involves a combination of antibiotic drugs that often leaves behind drug resistant strains. Dr. Sarah Fortune, an immunologist at the Harvard School of Public Health, and recipient of the NIH Director's New Innovator Award believes that the variation in the growth rate and size of mycobacterial cells (the causative agents of Tuberculosis) is a factor in how receptive the cells are to antibiotics.

Dr. Fortune and colleagues sought to measure the growth and antibiotic susceptibility of mycobacteria at the single cell level. The research team used live cell imaging techniques on fluorescently labeled Mycobacterium smegmatis (which is closely related to Mycobacterium tuberculosis) to observe the cells growing and replicating.

The research resulted in the discovery that the Mycobacterium smegmatis cells divided asymmetrically causing diversity in the subpopulation of cells. Noticeably, the divided subpopulation of cells differed in size and growth rate. The physiological differences in the cells led the researchers to speculate about the cells susceptibility to antibiotics. Thus, the subpopulations of cells were treated with various antibiotics. Dr. Fortune and colleagues reported that from the heterogeneous subpopulation of cells some of the cells were inherently tolerant to the antibiotics and some were not.

The researchers suggest that the variation of the subpopulation of cells could be an explanation as to why tuberculosis is difficult to cure. This research is a significant step towards understanding the properties and behavior of mycobacteria, which could improve Tuberculosis diagnosis, treatment, and prevention strategies.

Read the news article…

Read more about the NIH Director’s New Innovator Award program…..

References:

Aldridge BB, Fernandez-Suarez M, Heller D, Ambravaneswaran V, Irimia D, Toner M, Fortune SM. Asymmetry and Aging of Mycobacterial Cells Lead to Variable Growth and Antibiotic Susceptibility.Science, 2011.Dec15.PMID: 22174129


October 3, 2011
NEW MATERIAL HOLDS PROMISE FOR DRUG DELIVERY, MEDICAL IMPLANTS
Dr. Adah Almutairi, a 2009 NIH Director’s New Innovator awardee, and colleagues at the University of California San Diego, have developed a new type of “smart” polymeric material that may have widespread medical and biological applications.

 Reported in the journal Macromolecules, the new material disassembles in response to harmless levels of near infrared (NIR) irradiation, which can penetrate up to 10 centimeters (almost 4 inches) into the body. Both the material itself and its breakdown products are well-tolerated by living cells, suggesting this material would potentially be safe for use in humans.

This type of material could be used as a capsule for a drug, allowing doctors to only release the drug in a specific area, such as right next to a tumor. It could also be used in tissue engineering, implants, wound-healing, and biosensors. Dr. Almutairi and colleagues are now working on improving the design of this polymeric material, so that it becomes even more sensitive to NIR, allowing a more controlled disassembly of the material. This research is a significant step forward in the development of light-sensitive materials that will allow doctors and researchers to target previously inaccessible sites with precise spatial and temporal control.

Read the university news release…

Read more about the NIH Director’s New Innovator Award program…..

References:

Fomina N, McFearin CL, Sermsakdi M, Morachis JM, and Almutairi A. Low power, biologically benign NIR light triggers polymer disassembly. Macromolecules, 2011. 44: 8590-7. PMID: 22096258.


December 1, 2011
FOUR HUMAN MICROBIOME PROJECT (HMP) INVESTIGATORS HONORED BY ELECTION TO THE INSTITUTE OF MEDICINE
Four Human Microbiome Project (HMP) Investigators Honored by Election to the Institute of Medicine

Each year, the full membership of the IOM elects up to 65 new members and five foreign associates. Election to the IOM is one of the highest honors bestowed upon professionals in the fields of health and medicine. To be elected, individuals must display outstanding professional achievement and commitment to service. Membership in the IOM reflects the pinnacle of professional achievement. On October 17, 2011 in conjunction with its 41st annual meeting, new members for the class of 2011 were announced. Among the 65 newly elected members are four investigators supported by the NIH Common Fund Human Microbiome Project (HMP).

Martin J. Blaser, M.D., Frederick H. King Professor of Internal Medicine, chair, department of medicine, and professor of microbiology, New York University School of Medicine, is funded by the HMP to examine and evaluate the cutaneous microbiome in psoriasis.

Claire M. Fraser-Liggett, Ph.D., director, Institute for Genome Sciences, and professor of medicine, microbiology, and immunology, University of Maryland School of Medicine, has received two awards to study aspects of the human microbiome. She is focusing on the role of the gut microbiota in obesity in the Amish and also analyzing the structure and function of the human gut microbiota in Crohn's disease.

Richard A. Gibbs, Ph.D., Wofford Cain Professor, department of molecular and human genetics, and director, Human Genome Sequencing Center, Baylor College of Medicine, is funded to develop a microbial genome reference platform for metagenomics.

David A. Relman, M.D., Thomas M. and Joan C. Merigan Professor, departments of medicine and microbiology and immunology, Stanford University School of Medicine, has been awarded a grant aimed at optimizing a microfluidic device for single bacterial cell genomics.
Read more about the IOM class of 2011



November 8, 2011
EPIGENOMICS RESEARCHERS UNCOVER NEW CHEMICAL MODIFICATIONS ON DNA ASSOCIATED PROTEINS

Epigenetic marks are chemical modifications to the genome that regulate which genes are active and which proteins are made in a cell. These marks are found on DNA as well as on the histone proteins that DNA is wrapped around. Epigenetic marks help regulate the expression of genes involved in cell development and function, and are also implicated in a growing number of diseases such as cancer, diabetes, autoimmune diseases, and mental illness (see “A Scientific Illustration of How Epigenetic Mechanisms Can Affect Health”). Drs. Yingming Zhao and Bing Ren, supported in part by the Common Fund’s Epigenomics program, along with their colleagues, have expanded our understanding of epigenetics by identifying a wealth of novel histone modification sites, as well as histone modifications that have never been described before.

Using a combination of approaches in the most thorough examination of histones to date, the researchers identified 67 new histone modifications, increasing the number of known histone marks by about 70%. Some of these newly discovered histone marks correspond to types of chemical modifications that had already been described in other regions of histone proteins, but others represent an entirely new type of chemical modification of histones. One such novel modification, lysine crotonylation or Kcr, was found to label regions of the genome that are actively making proteins. In particular, Kcr modifications were found associated with genes that are activated in the testes of male mice at a specific time during development, suggesting that Kcr may regulate genes that are important for aspects of sperm cell maturation and function.

The discovery of these new histone modifications expands our understanding of epigenomics, and opens the door to further research into the epigenome that regulates health and disease.

Read more about the Epigenomics program…

Reference:

Tan M, Luo H, Lee S, Jin F, Soo Yang J, Montellier E, Buchou T, Cheng Z, Rousseaux S, Rajagopal N, Lu Z, Ye Z, Zhu Q, Wysocka J, Ye Y, Khochbin S, Ren B, and Zhao Y. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell, September 16, 2011. 146: 1016-28. PMID: 21925322.




HITTING THE TARGET: MOLECULE HONES IN ON CANCER CELLS
A major obstacle in the fight against cancer is finding treatments that target and kill only the cancerous cells without damaging healthy cells. Drs. Todd Golub and Stuart Schreiber, supported in part by the Common Fund’s Interdisciplinary Research Consortium for Genomic Based Drug Discovery, along with their colleagues, have discovered a molecule that can selectively kill cancer cells but does not harm normal cells.

As reported in the July 14 issue of Nature, this cancer-fighting molecule is piperlongumine, a natural product derived from the plant Piper longum (long pepper). Piperlongumine inhibited tumor growth in mice that were injected with human bladder, breast, lung, or melanoma cancer cells, as well as in mice genetically engineered to develop breast cancer, and it did so more effectively than the chemotherapy drug Taxol (paclitaxel). In both cell cultures and in mice, piperlongumine had no detectable toxic effects on healthy cells, even at extremely high concentrations.

The researchers found that piperlongumine works by targeting a cellular process that differs between cancer cells and normal cells. Cancer cells have a much higher rate of metabolism than normal cells, and consequently they have increased levels of toxic reactive oxygen species (ROS).

To tolerate high levels of ROS, cancer cells rely heavily on several different anti-oxidative enzymes that protect against these harmful molecules. Piperlongumine diminishes anti-oxidative enzyme activity, causing ROS levels in cancer cells to increase beyond the threshold for cell death. Normal cells, which have slower metabolic rates and lower levels of ROS, are not as dependent on these anti-oxidative enzymes and so are not harmed by piperlongumine.

These exciting results demonstrate a novel strategy for the treatment of cancer by targeting a previously unexplored cellular pathway, and may pave the way for future development of effective cancer drugs with limited side effects.

Read more about the Interdisciplinary Research program…
Read the news release

References:

Raj L, Ide T, Gurkar AU, Foley M, Shenone M, Li X, Tolliday NJ, Golub TR, Carr SA, Shamji AF, Stern AM, Mandinova A, Schreiber SL, and Lee SW. Selective killing of cancer cells by a small molecule targeting the stress response to ROS. Nature 2011; 475(7355):231-4. PMID: 21753854.



September 15, 2011
NEW UNDERSTANDING OF DANGEROUS FLU-RELATED COMPLICATION
The immune system is often thought of as an ally in the fight against invading pathogens that make us sick. But in the attempt to destroy pathogens, sometimes the immune system’s response can be more harmful than the invaders it is trying to defend against.

In the 1918 Spanish flu pandemic and the recent avian and swine flu outbreaks, scientists have proposed that an excessive immune reaction flooded patients’ lungs with fluid and disease-fighting cells, contributing to the abnormally high fatality rate. This severe immune reaction involves the production of large amounts of proteins called cytokines, and hence is often called a “cytokine storm.” Because cytokine storm can be deadly, medical interventions aimed at blunting this response are extremely desirable.

Recent work by Dr. Hugh Rosen, a researcher in the Common Fund’s Molecular Libraries and Imaging program, has led to a breakthrough in our understanding of the biological processes underlying cytokine storm. In a study published in the September 16, 2011 issue of Cell, Dr. Rosen and colleagues identify a small molecule compound that blocks cytokine storm and improves survival in mice infected with a strain of influenza virus that is normally fatal.

This compound interacts with a protein called S1P1, a receptor on the surface of cells that binds to specific molecules and elicits a cellular response. When the researchers treated influenza-infected mice with the compound, they discovered that the cytokine storm response was diminished and survival was improved. Intriguingly, the researchers also discovered that the cells coordinating cytokine storm were not immune cells or cells from the inner surface of the lungs, as was previously thought. Instead, the cytokine storm was mediated by endothelial cells, which line the inside of blood vessels.

These new insights about the role of endothelial cells and the S1P1 protein in the development of the cytokine storm response may help scientists predict which patients are most at risk for this potentially deadly complication, and also suggests potential new therapeutic targets for drug development efforts.

Read the news release
Read more about Molecular Libraries and Imaging program…

References:

Teijaro JR, Walsh KB, Cahalan S, Fremgen DM, Roberts E, Scott F, Martinborough E, Peach R, Oldstone MBA, and Rosen H. Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection. Cell, September 16, 2011. 146(6):980-991. PMID: 21925319

Iwasaki A and Medzhitov R. A new shield for a cytokine storm. Cell, September 16, 2011. 156(6): 861-2. PMID: 21925310.



August 19, 2011
NOVEL STEM CELL TECHNIQUE CREATES NEURONS
Drs. Kang Zhang and Sheng Ding, funded in part by the NIH Director’s Transformative R01 (T-R01) Award program, have unlocked the key to transforming human embryonic stem cells (hESCs) into a type of precursor cell that can be produced in large quantities and has the potential to become many different types of brain cells.

Their findings, published in the May 17, 2011 issue of Proceedings of the National Academy of Sciences, represent a huge leap forward in stem cell science. hESCs, with their ability to become any cell type in the human body, hold great potential for repairing or replacing damaged tissues. However, a number of obstacles have prevented hESCs from fulfilling this promise. Scientists have faced challenges finding the right method to change hESCs into more specialized precursor cells, which can self-renew to produce large quantities of cells while also retaining the ability to become many different cell types within a specific tissue.

Additionally, hESCs can cause the formation of tumors, which prohibits their use for therapeutic purposes. Drs. Zhang, Ding, and colleagues used a novel combination of small molecules to induce hESCs to become primitive neuronal stem cells (pNSCs), a cell type that can be directed to make many different types of neurons, or brain cells. Unlike hESCs, pNSCs did not induce tumor formation when injected into mice, which opens the door for potential therapeutic use.

The researchers coaxed the pNSCs to form the types of neurons damaged by Parkinson’s disease and Lou Gehrig’s disease (amyotrophic lateral sclerosis; ALS), and suggest that pNSCs could be used to make many other types of neurons as well. This same method could be modified to direct hESCs to make other types of stem cells that could then be used to make heart, pancreas, or other tissue types.  Future studies will need to examine how these cells could be used to treat a variety of human diseases.


Read more about the NIH Director’s Transformative R01 program...

Read the news release...

Reference:

Li W, Sun W, Zhang Y, Wei W, Ambasudhan R, Xia P, Talantova M, Lin T, Kim J, Wang X, Kim WR, Lipton SA, Zhag K, and Ding S. Rapid induction and long-term self-renewal of primitive neural precursors from human embryonic stem cells by small molecules inhibitors. Proceedings of the National Academy of Sciences, 2011 May 17; 108(20): 8299-8304. PMID: 21525408.



July 13, 2011
LOCATION, LOCATION, LOCATION: SCIENTISTS UNCOVER NEW INFORMATION ABOUT BRAIN STEM CELL ENVIRONMENT
The adult mammalian brain contains several specialized areas where stem cells capable of producing new neurons reside. Dr. Chay Kuo, an NIH Director’s New Innovator Award recipient, has identified key components of one such specialized area, or niche, that is critical for the production of new neurons. Published in the July 14, 2011 issue of Neuron, Dr. Kuo and colleagues demonstrate that two proteins, Foxj1 and Ank3, are critical for maintaining the cellular niche around brain stem cells.

Foxj1 is a transcription factor, a type of protein that regulates when and where other genes are expressed. Within the stem cell niche studied by Dr. Kuo, the Foxj1 protein causes the Ank3 protein to be expressed. The Ank3 protein then helps assemble groups of ependymal cells, a type of cell that surrounds the brain stem cells and provides support for the production of new neurons. Without Foxj1 and Ank3 proteins, the niche is disrupted and stem cells fail to produce new neurons.

Currently, when neural stem cells are studied in the laboratory, they are not surrounded by these ependymal cells. Under these conditions, it is extremely difficult to make the stem cells produce neurons. The findings of Dr. Kuo and colleagues suggests that in the laboratory setting, scientists may need to recreate the same kind of support provided by ependymal cells in the brain stem cell niche. By understanding the local cellular environment that helps support production of new neurons, researchers hope to improve future therapeutic strategies that use stem cells to produce neurons for repairing or replacing damaged tissue.

Read more about the NIH Director’s New Innovator Award program…..

Read the news release...

References:

Paez-Gonzalez P, Abdi K, Luciano D, Liu Y, Soriano-Navarro M, Rawlins E, Bennett V, Garcia-Verdugo JM, and Kuo CT. Ank3-dependent SVZ niche assembly is required for the continued production of new neurons. Neuron, July 14, 2011. 71: 61-75. PMID: 21745638.




OVERCOMING OBSTACLES TO ANALYZING COMPLEX BIOLOGICAL DATA
Biomedical research data generated from genomics analyses, imaging, biochemistry and other assays are abundant yet difficult to integrate using conventional approaches and databases.

To address this need, Dr. Peter Sorger and colleagues at Harvard Medical School, Massachusetts Institute of Technology, and the University of Applied Sciences in Germany, researchers supported through the Common Fund’s Library of Integrated Network Based Cellular Signatures (LINCS) program, have developed an innovative new adaptable method that allows different types of complex data sets to be stored, analyzed and extended.

In a recent paper in Nature Methods, they demonstrate the utility of the approach, which exploits useful aspects of two data file formats (HDF5 and XML), for analyzing a complex imaging data set reflecting 160 experimental conditions in over a million different single cells. The approach led to the discovery of new pharmacological relationships between compounds that bind and inhibit epidermal growth factor receptors (EGFR), providing insights into cell-to-cell variability in response to drugs.


References:

Millard BL, Niepel M, Menden MP, Muhlich JL, and Sorger PK. Adaptive informatics for multifactorial and high-content biological data. Nat Methods. 2011. Vol 8(6):487-493.



April 28, 2011
NEW COMPOUND TARGETS AUTOIMMUNE DISEASES
Researchers supported by the Molecular Libraries and Imaging program have helped to develop a novel chemical that blocks TH17 cells, immune cells implicated in numerous autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease.

Dr. Patrick Griffin and colleagues from the Scripps Research Institute Molecular Screening Center published a study in the April 28, 2011 issue of Nature describing SR1001, a new compound that blocks the development of TH17 cells and slows disease progression in a mouse model of multiple sclerosis.

TH17 cells are part of the body’s natural defense against disease-producing pathogens. However, in some autoimmune disorders, the inflammatory chemicals, or cytokines, produced by TH17 cells harm the body’s own tissues. SR1001 blocks TH17 cells by interfering with the action of two proteins critical for TH17 cell development, called RORα and RORγt. When SR1001 blocks the action of RORα and RORγt in the precursors to TH17 cells, these cells can no longer develop into TH17 cells and do not produce the cytokines normally produced by functioning TH17 cells.

Treatment with SR1001 delays disease onset and reduces the severity of symptoms in a mouse model of multiple sclerosis, a well-studied model for TH17-mediated autoimmune disease. These results suggest an exciting new way to target several different autoimmune disorders in which TH17 cells play a role.

Read more about the Molecular Libraries and Imaging Program...

References:

Solt LA, Kumar N, Nuhant P, Wang Y, Lauer JL, Liu J, Istrate MA, Kamenecka TM, Roush WR, Vidovic D, Schurer SC, Xu J, Wagoner G, Drew PD, Griffin PR, and Burris TP. Suppression of TH17 differentiation and autoimmunity by a synthetic ROR ligand. Nature, April 28, 2011. 472: 491-494. PMID: 21499262. Jetten AM. Immunology: A helping hand against autoimmunity. Nature, April 28, 2011. 472: 421-422. PMID: 21525918



March 14, 2011
FUELING STRUCTURE-BASED DRUG DISCOVERY
Researchers in the Common Fund’s Structural Biology program are changing the way companies are thinking about designing new drugs -- by using 3-D images of membrane proteins in cells to help identify and screen potential drug molecules.

 Membrane proteins span the membrane of cells and provide a pathway for signals outside the cell to be transmitted inside. G-protein-coupled receptors (GPCRs) are an important class of membrane proteins involved in many different biological pathways that are essential to health and response to therapeutics. Although almost 40% of all drugs on the market target GPCR signaling pathways, drug discovery remains slow and arduous because membrane proteins are very difficult to isolate, stabilize, and characterize structurally.

 Understanding the 3-D structure of a membrane protein can accelerate the discovery process because it shows all the “pockets” of the protein where molecules or drugs can bind and change how the protein signals to the inside of the cell. The structures can be used to test how a specific GPCR changes when it is bound by different molecules that may turn “on” or “off” the receptor.

While pharmaceutical companies are eager to get hold of 3-D crystal structures for GPRCs for use in drug discovery, they often find it difficult. A new trend reported in Chemical and Engineering News (March 14, 2011) shows drug companies are teaming up with academic researchers who have worked out these 3-D structures to overcome this problem.

Dr. Raymond Stevens and colleagues at the Scripps Research Institute, funded through the Structural Biology Program, have perfected a technique to stabilize and characterize the 3-D crystal structure of several GPCRs, including most recently, the A2A adenosine (A2A) receptor involved in control of inflammation and oxygen and blood flow through the heart. As reported in Sciencexpress (March 2011), the team developed an approach to stabilize the A2A receptor and then determine its 3-D crystal structure while a small “activator” molecule was bound to it.

The structure provides a view into how GPCRs become activated when bound by a specific small molecule. Having this 3-D structure for the A2A receptor enables drug companies to prioritize which small molecules to test first, for similar activity, during drug discovery. A company co-founded by Dr. Stevens adopted this technique and used it to successfully determine the structure of another GPCR, sphingosine-1-phosphate receptor subtype 1 (S1P1), involved in multiple sclerosis, a degenerative disease of the nervous system.

Recently, they identified a small molecule derived from a chemical “hit” discovered through the Common Fund’s Molecular Libraries and Imaging Program which effectively binds to and activates S1P1. The molecule is being tested further as a potential new therapy for multiple sclerosis. The synergy between the two programs, Structural Biology and Molecular Libraries and Imaging, represents a growing trend in partnerships between academic and private sector researchers to tackle difficult problems in drug discovery.

Read the news articles….
http://pubs.acs.org/cen/coverstory/89/8911cover.htmlc
http://pubs.acs.org/cen/coverstory/89/8911cover1.html
http://www.sciencemag.org/content/early/2011/03/09/science.1202793

Read more about the drug discovery process for RP1063...
Read more about the Structural Biology program..
Read more about the Molecular Libraries and Imaging Program...




March 10, 2011
MOUSE GENETICS LEADS TO NEW CLUES FOR HUMAN PSYCHIATRIC DISORDERS

Several psychiatric disorders, including attention deficit hyperactivity disorder (ADHD), drug and alcohol addiction, and schizophrenia, are characterized by poor impulse control and difficulty inhibiting certain behaviors. These traits are referred to as behavioral inflexibility, which is thought to be partially under genetic control. However, the genes responsible have been difficult to identify in humans. In a paper available online March 10, 2011 in the journal Biological Psychiatry, researchers in the Common Fund’s Interdisciplinary Research program’s Consortium for Neuropsychiatric Phenomics report that they have identified several genes associated with behavioral inflexibility in mice, and that these findings might be applicable to humans as well.

o identify genes that underlie behavioral inflexibility, Dr. David Jentsch and colleagues from the University of California Los Angeles and the University of Tennessee first tested 51 genetically different strains of mice for the ability to reverse their behavior in a learned task. To successfully complete this task, mice had to learn to poke their nose into an opening either on the left or right side of the cage in order to receive a food reward. Once the mice mastered this skill, they had to unlearn which side to poke their nose into, and re-learn to poke their nose on the opposite side.

The number of tries it takes a mouse to reverse its behavior indicates how much behavioral flexibility and impulse control the mouse has. The researchers reasoned that by looking at both the genes and behaviors of the mice, they could find genetic differences that were associated with the behavioral differences. Indeed, the researchers zeroed in on a region of the mouse chromosome 10 that contains several genes that influence behavioral flexibility. One gene, Syn3, regulates chemical communication in the brain and has been inconclusively linked to schizophrenia in humans. Another gene, Nt5dc3, is a gene of unknown function that has been associated with ADHD. The current research suggests that both of these genes should be investigated further to discover what role they may play in human psychiatric disorders, and also demonstrates a new way to use mouse behavior and genetics to find genes that may contribute to complex behaviors in humans.

Read more about the Interdisciplinary Research program…


Reference:

Laughlin RE, Grant TL, Williams RW, Jentsch JD. Genetic dissectioin of behavioral flexibility: reversal learning in mice. Biological Psychiatry, 2011 June 1; 69(11): 1109-16. Epub 2011 March 9. PMID: 21392734.


March 3, 2011
SCIENTISTS UNCOVER HOW TUBERCULOSIS “PUMPS-UP” TOLERANCE TO DRUG THERAPIES

Shortening the time required to treat tuberculosis (TB) is key to reducing the development of drug resistance and lowering worldwide rates of TB infection and mortality. Reducing treatment duration however depends on: (1) understanding how Mycobacterium tuberculosis (Mtb), the bacteria that causes TB in humans, becomes tolerant to antibiotics; and (2) devising ways to prevent or overcome drug tolerance. NIH Director’s Pioneer Award recipient Dr. Lalita Ramakrishnan and colleagues at the University of Washington, in collaboration with Dr. Paul Edelstein at the University of Pennsylvania, report in a study appearing in the April 1, 2011 issue of Cell, that the development of drug tolerance in Mtb is due in part to the activity of “efflux” pumps in the cell membrane that presumably flush away any antibiotic agents that penetrate the Mtb cells.

The authors found that these pumps are stoked into action by host cells called macrophages that are, ironically, part of the body’s frontline defenses against foreign invaders. Based on these findings, the study authors suggest that expanding treatment to include medications that inhibit these pumps could dramatically shorten the time needed to cure infection. While Mtb can infect many body tissues and organs, it primarily attacks the lungs.

Once inside the lungs, the bacteria infect the aforementioned macrophages. The macrophages and other types of immune cells respond by aggregating into structures called granulomas which are thought to contain the spread of persistent pathogens. Having taken up residence within macrophages, some populations of Mtb cells quickly become tolerant to anti-TB drugs. Nearly all models of Mtb drug tolerance postulate that this temporary resistance to antibiotics arises when the bacterial cells enter a dormant state in which they stop replicating. Because most antibiotics are only effective against bacterial cells that are reproducing, dormant cells are effectively resistant to antimicrobial agents.

In their latest paper however, Dr. Ramakrishnan and colleagues report finding multi-drug tolerant Mtb populations that were actively growing and reproducing inside of host macrophages suggesting that residence within macrophages rapidly induces tolerance. The study authors also found that, having infected macrophages, the Mtb cells deploy effNovel Blood ux pumps that are essential for the Mtb cells to grow within the macrophages and may be used by the bacterial cells to remove toxic substances such as antimicrobial agents.

 In addition to expanding our understanding of the pathogenesis of TB and drug tolerance, these findings suggest that inhibiting the activity of macrophage-induced bacterial efflux pumps using currently available drugs such as verapamil may be an effective means of reducing the duration of TB treatment. Shorter treatment is likely to translate into increased adherence which will in turn slow the development of multi-drug resistance, reduce transmission of infection to new hosts, and reduce TB-associated mortality around the world.

Read the press release...
Read the paper...
Read more about the Pioneer Award program...


Reference:

Adams KN, Takaki K, Connolly LE, Wiedenhoft H, Winglee K, Humbert O, Edelstein PH, Cosma CL, Ramakrishnan L. Drug tolerance in replicating mycobacteria mediated by a macrophage-induced efflux mechanism. Cell, 2011 April 1; 145(1): 39-53. PMID: 21376383.


February 3, 2011
EMBRYONIC AND INDUCED-PLURIPOTENT STEM CELLS REVEAL OWN MOLECULAR SIGNATURE

New discoveries in stem cell biology are fueling the development of new cell-based therapies for diseases such as Parkinson’s and diabetes where tissues may become diseased or damaged. Before this potential can be reached, an important, yet unanswered question is whether adult cells that are “induced” to become like embryonic stem cells – so called induced pluripotent stem cells (iPS cells) -- are actually equivalent to embryonic stem cells and can be used in cell-based therapies.

Researchers in the Common Fund’s Epigenomics program are tackling this question. In the February 3, 2011 issue of Nature, Dr. Joseph Ecker and colleagues at the Salk Institute investigated this question by comparing the pattern or “fingerprint” of DNA modifications made by the attachment of a methyl group to a specific DNA base across the genome in iPS cells, human embryonic stem cells, and iPSCs that are coaxed to “return to adulthood.”

They found that pattern of DNA methylation for iPS cells is different from true human embryonic stem cells, especially in the middle and ends of the chromosome. At other locations along the genome, the DNA methylation pattern in the iPS cells was similar to that of the adult cells and was retained when the iPS cells were converted back to their “adult” state. Because DNA methylation helps to control gene activity in a cell, the differences in methylation pattern across cell types signal that iPS cells may have a unique molecular “identity” compared to embryonic stem cells. Understanding these differences between iPS and embryonic stem cells is an important step toward harnessing the potential of iPS cells to treat injury and disease.

Read the press story...
Read more about the Epigenomics program...

Reference:

Lister R, Pelizzola M, Kida YS, Hawkins RD, Nery JR, Hon G, Antosiewicz-Bourget J, O’Malley R, Castanon R, Klugman S, Downes M, Yu M, Stewart R, Ren B, Thomson JA, Evans RM, and Ecker JR. Hotspots of aberrant epigenomic reprogramming in human induced pluripotent stem cells. Nature. Mar 2011. 471:68–73. PMID: 21289626



January 27, 2011
FROM THE LAB TO THE CLINIC: DISCOVERY FROM MOLECULAR LIBRARIES PROGRAM ENTERS CLINICAL TRIALS

Researchers in the Common Fund’s Molecular Libraries and Imaging program are tackling a tough biological problem—finding potential drug candidates that target G protein-coupled receptors (GPCRs). Dr. Hugh Rosen, funded in part by the Molecular Libraries and Imaging program, is a scientific founder of Receptos, Inc., a GPCR drug discovery and development company. GPCRs are proteins found on the cell membrane that transmit signals from the outside of the cell to elicit responses inside the cell.

GCPRs play many important roles in the body, including hormone signaling, cellular communication in the brain, vision, and cardiac function. Because GPCRs are crucial to many biological processes, they are also implicated in a number of different diseases. One such GPCR, called sphingosine-1-phosphate receptor 1 (S1P1), plays a role in multiple sclerosis, an inflammatory and autoimmune disease which causes damage to the protective myelin sheaths of nerve cells and to the underlying nerve fibers. The current focus of Receptos, Inc. is to conduct clinical trials for a novel compound that targets S1P1, called RPC1063, in the hopes that this potential treatment will suppress circulating immune cells to blunt the underlying cause of multiple sclerosis.

The discovery of this novel compound originated from the Molecular Libraries and Imaging program. The first phase 1 clinical safety study of RPC1063 was launched in January 2011, and Phase 2 Proof of Concept studies are expected in 2012. This research has the potential to improve the treatment of multiple sclerosis, and many other diseases that involve signaling by GPCRs.
Read Receptos news release…
Read more about Molecular Libraries and Imaging program…
Reference:

Reddy MM, Wilson R, Wilson J, Connell S, Gocke A, Hynan L, German D, Kodadek T. Identification of candidate IgG biomarkers for Alzheimer’s disease via combinatorial library screening. Cell, 2011 Jan 7; 144(1): 132-42. PMID: 21215375.




January 7, 2011

NOVEL BLOOD TEST MAY IMPROVE DIAGNOSIS OF MANY DISEASES

While simple blood tests can accurately and efficiently screen for some diseases, such as diabetes, the lack of blood tests for the majority of diseases can result in delayed or incorrect diagnoses. To overcome this diagnostic obstacle, Dr. Thomas Kodadek, a researcher at The Scripps Research Institute and funded in part by an NIH Director’s Pioneer Award, has developed a novel screening method that could detect disease-associated proteins in the blood of patients with a variety of conditions.

In the January 7, 2011 edition of the journal Cell, Dr. Kodadek and colleagues describe their technique for using a collection of synthetic molecules to detect the presence of unique proteins in the blood of diseased individuals that do not appear in the blood of healthy individuals. By screening blood samples from mice with multiple sclerosis, the researchers identified several molecules in their synthetic collection that would only bind to proteins in the blood of the diseased mice, and could distinguish between “patient” mice and normal, healthy mice.

Importantly, the researchers went on to demonstrate that in samples from humans, they could use the same technique to identify different molecules that bound to proteins uniquely present in the blood of patients with Alzheimer’s disease. This same binding did not occur in samples from healthy people of similar ages or in patients with another neurodegenerative disorder, Parkinson’s disease. These promising results suggest that this type of blood test has the potential to screen for a wide variety of different diseases, including diseases that currently lack a reliable diagnostic test.
Read News Release...

Read more about NIH Director’s Pioneer Awards...
Reference:

Reddy MM, Wilson R, Wilson J, Connell S, Gocke A, Hynan L, German D, Kodadek T. Identification of candidate IgG biomarkers for Alzheimer’s disease via combinatorial library screening. Cell, 2011 Jan 7; 144(1): 132-42. PMID: 21215375.




December 7, 2010
SCIENTISTS UNCOVER NEW PROCESS REGULATING ELECTRICAL FIRING PROPERTIES OF NEURONS

Neurons in the brain communicate with each other using a combination of carefully regulated chemical and electrical signals. NIH Director’s Pioneer Award recipient Dr. James Eberwine and colleagues at the University of Pennsylvania and Sequenom, Inc. have discovered a novel method by which neurons selectively express proteins that control their electrical properties , reported in the December 7, 2010 issue of the Proceedings of the National Academy of Sciences.

In neurons, electrical signals are controlled by channel proteins that create a pore in the cell membrane to allow positively or negatively charged ions to flow in and out of the cell. One of these channel proteins, called BKCa, helps regulate electrical signals in the hippocampus, an area of the brain that is important for learning and memory. Interestingly, the hippocampus is also the focus of many epileptic seizures, which result from disturbances in the electrical firing of neurons.

The BKCa channel protein has several different variations. These protein variations arise during a cellular process called “splicing,” which is analogous to the process of cutting an undesired segment out of an audiotape and joining the resulting ends together. To make a protein, a cell must identify the piece of DNA that contains the instructions for the protein (called a gene), copy the DNA into another form of genetic material, called RNA, and then use the information encoded in the RNA to make the protein.

Often, the instructions in the DNA for making a protein are not in a continuous stretch, but contain intervening sequences or “introns.” After the DNA is copied into RNA, these introns are removed and the flanking coding sequences, or “exons,” are connected to each other. It is the sequence of merged exons that tells the cell how to make a protein. Since the RNA can be spliced in different ways, one gene sequence can be used to make several different protein variants, depending on which exons are included. Normally splicing takes place in the nucleus of a cell, the cell’s control center where the DNA is stored.

However, previous work from Dr. Eberwine’s lab has shown that splicing can also occur outside the nucleus, in a neuron’s cytoplasm. Dr. Eberwine’s latest paper demonstrates for the first time that one of the introns removed during cytoplamic splicing can regulate which form of BKCa channel protein is made, which in turn affects important electrical properties of the neuron. While introns used to be considered “junk DNA,” a number of studies, including Dr. Eberwine’s papers, are demonstrating that introns play crucial regulatory roles. Studying the process of splicing and intron removal in the production of BKCa channels may provide new insights about disorders of neuronal misfiring, such as epilepsy.

Read News Release...
Read more about NIH Director’s Pioneer Awards...
Reference:

Bell TJ, Miyashiro KY, Sul JY, Buckley PT, Lee MT, McCullough R, Jochems J, Kim J, Cantor CR, Parsons TD, Eberwine JH. Intron retention facilitates splice variant diversity in calcium-activated big potassium channel populations. Proceedings of the National Academy of Sciences, 2010 Dec 7; 107(49): 21152-7. PMID: 21078998.





HANDBOOK FOR SMALL MOLECULE PROBES

The Molecular Libraries Program (MLP), a component of the NIH Common Fund, offers public sector biomedical researchers access to the large-scale screening capacity necessary to identify small molecules that can be optimized as chemical probes to study the functions of genes, cells, and biochemical pathways. This will lead to new ways to explore the functions of genes and signaling pathways in health and disease.

The Molecular Libraries Probe Production Centers Network (MLPCN), as part of the MLP, is a nationwide consortium of small molecule centers that produces innovative chemical tools for use in biological research.

 The MLPCN solicits novel assays from the research community for high throughput screening (HTS) against a library of 350,000 chemically diverse small molecules maintained in a central repository (the Molecular Libraries Small Molecule Repository; MLSMR). Validated screening hits are optimized by medicinal chemistry to produce useful in vitro chemical probes. All of the results from the MLPCN’s activities are deposited into an open access database, PubChem, for use in studying biology and disease.

The MLPCN brings together over 100 experienced medicinal chemists from five academic institutions and one NIH intramural center to focus on the development of high quality probes from screening hits. The lead medicinal chemists have extensive industrial experience from both biotech and large pharmaceutical companies. MLPCN probes cover highly diverse targets, biology and disease areas with many probes moving on as potential leads in drug discovery efforts after exiting the MLPCN.

This book brings together structure and biological information on the probes produced by the MLPCN in collaboration with the investigators who provided the screening assays. This information will be periodically updated with new probe information from the active MLPCN Centers.
Read News Release...



December 1, 2010
UNLOCKING THE MYSTERIES OF PROTEIN STRUCTURE FOR BETTER DRUG DEVELOPMENT


Researcher Uncovers Shape of Protein Important for Neurological Disorders
The Joint Center for Integral Membrane Protein Technologies-Complexes (JCIMPT-Complexes) at the Scripps Research Institute headed by Dr. Raymond C. Stevens, funded in part by the Common Fund's Structural Biology program, has determined the three-dimensional shape of D3R, a protein that binds to dopamine and is implicated in schizophrenia, Parkinson's disease, and drug addiction
Read more...
Read more about the Structural Biology program...

Reference:

Chien EY, Liu W, Zhao Q, Katritch V, Han GW, Hanson MA, Shi L, Newman AH, Javitch JA, Cherezov V, Stevens RC. Structure of the human dopamine D3 receptor in complex with a D2/D3 selective antagonist. Science 2010 Nov 19; 330(6007): 1091-5. PMID: 21097933.

Researcher Determines Shape of a Protein Important for HIV and Cancer
Dr. Raymond C. Stevens and colleagues at The Joint Center for Integral Membrane Protein Technologies-Complexes (JCIMPT-Complexes) have determined the three-dimensional structure of CXCR4, a cellular protein important for HIV infection as well as the growth and metastasis of many types of cancer.

Read more...
Read Press Release...
Read more about the Structural Biology program...
Reference:

Wu B, Chien EY, Mol CD, Fenalti G, Liu W, Katritch V, Abagyan R, Brooun A, Wells P, Bi FC, Hamel DJ, Kuhn P, Handel TM, Cherezov V, Stevens RC. Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science 2010 Nov 19; 330(6007): 1066-71. PMID: 20929726.


November 30, 2010
SWEET DISCOVERY FOR PLANTS...AND HUMANS
Similar to humans, plants can be sickened by infection with bacteria and other pathogens, resulting in crop losses of over $500 billion every year. In the November 24th online edition of the journal Nature, Dr. Wolf Frommer of the Carnegie Institution and funded in part by the Common Fund’s Metabolomics Technology Development program, has identified how pathogens "hijack" plant cells to steal nutrients for their own use and discovers a potential novel target for blocking a broad range of pathogenic plant infections.
Read more...
Read more about the Metabolomics program...
Reference:

Chen LQ, Hou BH, Lalonde S, Takanaga H, Hartung ML, Qu XQ, Guo WJ, Kim JG, Underwood W, Chaudhuri B, Chermak D, Antony G, White FF, Somerville SC, Mudgett MB, Frommer WB. Sugar transporters for intracellular exchange and nutrition of pathogens. Nature, 2010 Nov 25; 468(7323): 527-32. PMID: 21107422.



November 22, 2010



NEW COMPOUND PREVENTS WEIGHT GAIN IN MICE
Dr. Jef Boeke at Johns Hopkins University, funded in part by the Common Fund's Technology Centers for Networks and Pathways (TCNP) program, has designed a compound that reduces weight gain in mice fed a high fat diet. In a paper published in the November 18th advance online edition of the journal Science, Dr. Boeke and colleagues show that the compound, called GO-CoA-Tat, interferes with the action of ghrelin, a hormone released from the gut that promotes weight gain. In order to function, ghrelin must be activated by another protein called GOAT (ghrelin O-acyltransferase).

However, GO-CoA-Tat binds to GOAT and prevents it from activating ghrelin. Mice injected with GO-CoA-Tat had less activated ghrelin and gained less weight on a high fat diet than mice that received a placebo. Treatment with GO-CoA-Tat also improved the insulin response of the mice to a dose of glucose, a test similar to that used in humans to diagnose diabetes. Interestingly, mice treated with GO-CoA-Tat ate the same amount as mice treated with placebo, suggesting that GO-CoA-Tat regulates metabolism and not appetite.

This study suggests a potential new drug target for the treatment of disorders such as diabetes, metabolic syndrome, and obesity.
Read more about the TCNP program...
Reference:

Barnett BP, Hwang Y, Taylor MS, Kirchner H, Pfluger PT, Bernard V, Lin YY, Bowers EM, Mukherjee C, Song WJ, Longo PA, Leahy DJ, Hussain MA, Tschop MH, Boeke JD, Cole PA. Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science, 2010 Dec 17; 330(6011): 1689-92. Epub 2010 Nov 18. PMID: 21097901.

November 4, 2010
COMMON FUND AWARDS $38.4M IN ARRA FUNDS IN FISCAL YEAR 2010
In fiscal year 2010, the NIH Common Fund made nine new American Investment and Recovery Act (ARRA) awards totaling $38.4M. All nine awards are “Building Sustainable Community-linked Infrastructure to Enable Health Science Research” grants (RC4) and each proposes a highly innovative program of research that cuts across multiple thematic areas for the NIH. Read More...




October 29, 2010
NEURONS FILTER OUT IRRELEVANT INFORMATION

Scientists have discovered how a small subset of neurons in the zebrafish brain has a big impact on an important behavior—the ability to hunt down prey. In a study published in the October 29th issue of Science, Dr. Herwig Baier of UC San Francisco and Dr. Ehud Isacoff of UC Berkeley, investigators in the Common Fund’s Nanomedicine program, use a novel fluorescent reporter of nerve cell activity to uncover how zebrafish can spot a tiny, one-celled paramecium against a complex visual background.

The optic tectum in zebrafish is a layered structure that receives signals from the eye in the superficial layer, and sends signals from the deeper layer out to motor areas of the brain that control movement. Drs. Baier and Isacoff and colleagues demonstrate that a group of neurons in the optic tectum called superficial inhibitory neurons (SINs) acts to "filter out" large background patterns, allowing the tectum to send specific messages to motor areas about small, moving objects like prey. Silencing or destroying SINs eliminates this filtering, and impairs the zebrafish’s ability to catch prey.

The selective filtering of irrelevant background information is found throughout the brain of many animals, including humans, but relatively little is known about the individual nerve cells that underlie this process. This study offers important insight about how circuits of nerve cells can provide background filtering, and suggests similar mechanisms may be found in human brains.
Read more about the Nanomedicine program...
Reference:

Del Bene F, Wyart C, Robles E, Tran A, Looger L, Scott EK, Isacoff EY, Baier H. Filtering of visual information in the tectum by an identified neural circuit. Science, 2010 Oct 29; 330 (6004): 669-73. PMID: 21030657.



October 13, 2010

HIGH THROUGHPUT STRATEGY FOR TESTING NERVE REGENERATION

Finding new drugs to promote regeneration of damaged nerve cells holds great promise for diseases such as Alzheimer's disease, spinal cord injury, brain trauma, and more. Many potential treatments, while promising in cell cultures, fail to promote regeneration in living animals.

 In a paper published October 13th in the Early Edition of the Proceedings of the National Academy of Sciences, Dr. Mehmet Yanik, a researcher at the Massachusetts Institute of Technology and an NIH Director's New Innovator awardee, demonstrates a novel method to rapidly screen potential drugs for their ability to promote nerve regeneration in the nematode C. elegans.

Using this method, Dr. Yanik and colleagues discovered that compounds which regulate protein kinase C (PKC), an enzyme important for many different cellular processes, can modulate nerve regeneration after injury in specific neurons. The ability of this method to efficiently screen large numbers of potential drugs in living animals may greatly accelerate the discovery of new treatments to promote nerve regeneration.

Read more about New Innovators Awards...
Reference:

Samara C, Rohde CB, Gilleland CL, Norton S, Haggarty SJ, Yanik MF. Large-scale in vivo femtosecond laser neurosurgery screen reveals small-molecule enhancer of regeneration. Proceedings of the National Academy of Sciences, 2010 Oct 26; 107(43): 18342-7. Epub 2010 Oct 11. PMID: 20937901.



October 6, 2010

EARLY INDEPENDENCE AWARDS JUMP START RESEARCH INDEPENDENCE
The National Institutes of Health announces the establishment of the NIH Director´s Early Independence Award (EIA) Program, a $60 million, 5-year initiative to support junior investigators in independent academic positions immediately following completion of their graduate research degrees. The NIH expects to issue 10 awards through this program in fall 2011.

The EIA Program is intended to support exceptional early career scientists who possess the intellect, scientific creativity, drive, and maturity to flourish independently without the need for traditional post-doctoral training. The EIA grantees will be able to begin highly innovative and bold research programs as early in their careers as possible, increasing productivity and spurring pioneering research. NIH Director, Dr. Francis Collins, speaks out about the new initiative in a commentary in Nature, Vol.467, 7 October 2010.

Read Press Release...
Read more about the Early Independence Awards Program...
Join the discussion on the Early Independence Awards Program...


2010
DUAL NIH HONORS: TWO RESEARCHERS RECEIVE PIONEER AND T-R01 AWARDS
TrT
Treating a Parkinson's disease- like syndrome in rats using electrical stimulation of the spinal cord.

Miguel A. Nicolelis, M.D., Ph.D., neurobiologist and professor of neurobiology, biomedical engineering, and psychology and neuroscience at Duke University, will use the T-R01 Award to study dorsal spinal column stimulation as a novel alternative treatment of Parkinson's disease that is minimally invasive, easy to perform, and inexpensive. For his research under the Pioneer Award he will develop the first shared brain-controlled virtual reality environment designed to investigate brain-actuating technologies for treating neurological disorders.


Schematic representation depicting specific binding of genomic loci by Zinc Finger proteins, and light-tunable modulation of gene expression.J. Keith Joung, M.D., Ph.D., pathologist at Massachusetts General Hospital and professor of pathology at Harvard Medical School, is a molecular biologist with interests in protein engineering and molecular recognition.

His Pioneer Award research will allow him to pursue developing more efficient methods for the generation, alteration, and differentiation of pluripotent stem cells. These broadly applicable approaches should accelerate the use of human stem cells for modeling of biological systems and for regenerative molecular medicine.

His research under the T-R01 Award with fellow team members Paola Arlotta, Ph.D. at Massachusetts General Hospital / Harvard Medical School and Feng Zhang, Ph.D. at Massachusetts Institute of Technology will identify and apply new technologies that use molecular regulators to regenerate specific components of the nervous system and treat neurodegenerative diseases.

Read more about NIH Director’s Pioneer Awards...
Read more about NIH Director’s TR01 Awards...




October 4, 2010
MILLIONS IN COMMON FUND AWARDS IN FY 2010
NIH Common Fund supports new research projects that cut across scientific disciplines and challenges conventional thinking.



September 13, 2010
GUT MICROBES CHANGED BY REPEATED ANTIBIOTIC USE

Repeated use of the antibiotic ciprofloxacin (Cipro) leads to persistent changes in the beneficial microbes of the gut, according to a study by David Relman, a researcher at Stanford University and recipient of an NIH Director's Pioneer Award.

While ciprofloxacin usually does not cause gastrointestinal side effects normally associated with disturbance of gut-dwelling bacteria, this research demonstrates the occurrence of more subtle changes in gut microbe composition, such as replacement of some bacterial species with closely related species or eradication of some sub-sets of bacteria, particularly when multiple courses of antibiotics are administered.

These long-term, persistent changes in microbe composition raise concerns about the evolution of antibiotic-resistant bacteria as well as chronic changes in pathogen-host interactions in the gut, regulation of host immunity, energy balance, or metabolism.

Read News Release...
Read more about NIH Director’s Pioneer Awards...
Reference:

Dethlefsen L, Relman DA. Incomplete recovery and individualized responses of the human distal gut microbiota to repeated antibiotic perturbation. Proceedings of the National Academy of Sciences, 2011 Mar 15; 108 Suppl 1: 4554-61. Epub 2010 Sep 16. PMID: 20847294.




July 20, 2010
GENDER OF ALCOHOLIC PARENTS AND THEIR CHILDREN AFFECT PREVALENCE OF PSYCHIATRIC ILLNESS

Both the gender of an alcoholic parent and the gender of their children can affect the likelihood of those children developing certain types of psychiatric illness, according to a study by Marc Potenza and colleagues at Yale University School of Medicine, part of the Yale Center for Clinical Investigation supported by the Common Fund's Clinical and Translational Science Awards (CTSAs).

While having an alcoholic parent of either gender increases a child's overall risk of developing a psychiatric illness, the risk of certain illnesses was affected by the gender of parent and child. For example, the odds of developing mania were significantly higher when the alcoholic parent and the child were of the same gender—i.e. sons of alcoholic fathers and daughters of alcoholic mothers.

Other disorders showed an opposite gender effect—daughters of alcoholic fathers had an increased risk of abusing alcohol compared to sons, while sons of alcoholic mothers had an increased risk of panic disorder compared to daughters. Understanding how gender may influence risk of psychiatric illness in families with parental alcoholism may have important implications for prevention and treatment of at-risk children.

Read News Release...
Read more about CTSAs...
Reference:

Morgan PT, Desai RA, Potenza MN. Gender-related influences of parental alcoholism on the prevalence of psychiatric illnesses: analysis of the National Epidemiologic Survey on Alcohol and Related Conditions. Alcoholism: Clinical and Experimental Research, 2010 Oct; 34(10): 1759-67. Epub 2010 Jul 20. PMID: 20645936.




July 8, 2010
NEW FY11 COMMON FUND PROGRAMS
New research programs, supported through the NIH Common Fund, are being launched in Fiscal Year 2011 to address critical needs and opportunities in a number of cross-cutting areas:

Gulf Oil Spill
HMO Collaboratory
NIH Director´s Early Independence Award
Health Economics
Planning Activities in FY2011
New Models for Large Prospective Studies


June 17, 2010
TINY DEVICE HELPS VIEW PROTEIN STRUCTURE

Dr. Rustem Ismagilov and colleagues at the University of Chicago have engineered a tiny microfluidic device called the “SlipChip” that optimizes the conditions for proteins to form crystals, enabling researchers to study how the proteins function normally in cells and become disrupted in disease. Read more...


OVERCOMING OBSTACLES IN RESEARCH CULTURE: Q&A WITH DR. XAVIER CAGIGAS

The Common Fund´s Interdisciplinary Research Consortium proves successful at facilitating interdisciplinary approaches that dissolve academic department boundaries within academic institutions, increase cooperation between institutions, train scientists working at the interface of disciplines, and build bridges between biological sciences and behavioral and social sciences. Read the story...




March 2010
INNOVATIVE APPROACHES TO STUDY COMPLEX SIGNALING PATHWAYS IN CELLS

Researchers at John Hopkins University, led by Dr. Toru Komatsu and supported through the Common Fund’s Molecular Libraries and Imaging program, have developed a novel system to target and perturb specific molecular activities and communications pathways within cells. The technique may help elucidate the structure and function of complex signaling networks that perform basic functions within cells and may someday be targeted in disease therapies. The work was published in the journal Nature Methods (2010, 7(3):206-208).


Read more about this paper and view other program publications…



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Division of Program Coordination, Planning, and Strategic Initiatives  •  National Institutes of Health  •  Bethesda, Maryland 20892
   

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