Structural Genomics of Orphan Nuclear Receptors

Summary

Principal Investigator: H Eric Xu
Abstract: DESCRIPTION (provided by applicant): The long-term objective of this project is to determine the structures of all orphan nuclear receptor ligand binding domains (LBDs), to correlate their structures with the biological functions of these receptors, and to explore the structural information for discovery of drugs that target these receptors. Nuclear receptors (NRs) constitute a large family of DNA-binding transcription factors that modulate the expression of genes involved in a broad spectrum of physiology. In contrast to other transcription factors, the activity of NRs is regulated by small-molecule ligands that directly bind NRs to induce active or repressive conformations. Their regulation by small molecules has made NRs one of the most important and successful targets for therapeutic drugs. All nuclear receptors contain at least one of two highly conserved domains: the centrally located DNA-binding domain (DBD) and the C-terminal LBD. The LBD is the key structural and functional domain of a NR. In addition to ligand binding, the LBD contains dimerization motifs and a conserved surface that mediates ligand-regulated recruitment of coactivators and co-repressors for transcriptional regulation. The LBD has thus been the focus of intense structural study and the direct target of pharmaceutical discovery. Crystal structures of all "classical" endocrine nuclear receptors and all "adopted orphan receptors" (receptors for which ligands were identified after the receptor was identified) have been solved. These structures reveal a conserved sandwich fold that harbors a ligand binding pocket and a C-terminal activation helix (AF-2) that mediates the ligand-regulated function of nuclear receptors. Importantly, these structures have been instrumental in revealing key mechanisms of ligand regulation and ligand discovery for nuclear receptors, as demonstrated for SF-1 and COUP-TFII in the first period of this grant. Currently, there are only three subfamilies (SHP, GCNF, and TLX/PNR) of human nuclear receptors for which the LBD structure remains to be solved. SHP, GCNF, TLX, and PNR are essential regulators in cholesterol homeostasis, neurogenesis, eye development, and stem cell regeneration, respectively, but little is known about their structures and ligand regulation. The lack of structural information has become a critical barrier for understanding the biology and signaling pathways mediated by these receptors. Based on ligand identification for other orphan nuclear receptors and the common structural features of nuclear receptors, we hypothesize that the remaining orphan nuclear receptors (SHP, GCNF, TLX/PNR) are also ligand-regulated. In this renewed application, the plan is to use X-ray crystallography in combination with biochemical and functional assays to test this hypothesis. Achieving our specific aims will overcome the above critical barrier to scientific advancements related to these receptors by providing a comprehensive structural and molecular framework for ligand regulation of these receptors, as well as a knowledgeable foundation for drug discovery focused on targeting these receptors. PUBLIC HEALTH RELEVANCE: SHP, TLX/PNR, and GCNF are orphan nuclear receptors that play crucial roles in the metabolism of lipids and bile acid, or maintenance and development of neural and embryonic stem cells. However, little is known about their structures and aspects of ligand regulation. The lack of structural information for these receptors has become critical barriers to progress of these receptors. Crystal structures of these receptors and their functional correlation under their respective biological context will not only establish whether these orphan nuclear receptors are ligand-regulated receptors, but will also serve as a rational template for drug design targeting of these receptors for cancers, metabolic diseases, and stem cell therapy for neurodegenerative diseases.
Funding Period: 2005-08-01 - 2014-08-31
more information: NIH RePORT

Top Publications

  1. pmc A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist
    W David Tolbert
    Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, Grand Rapids, MI 49503, USA
    Proc Natl Acad Sci U S A 104:14592-7. 2007
  2. pmc Identification of a lysosomal pathway that modulates glucocorticoid signaling and the inflammatory response
    Yuanzheng He
    Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, MI 49503, USA
    Sci Signal 4:ra44. 2011
  3. pmc Identification and mechanism of 10-carbon fatty acid as modulating ligand of peroxisome proliferator-activated receptors
    Raghu R V Malapaka
    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503, USA
    J Biol Chem 287:183-95. 2012
  4. pmc Structural conservation of ligand binding reveals a bile acid-like signaling pathway in nematodes
    Xiaoyong Zhi
    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
    J Biol Chem 287:4894-903. 2012
  5. pmc Structure and mechanism for recognition of peptide hormones by Class B G-protein-coupled receptors
    Kuntal Pal
    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503, USA
    Acta Pharmacol Sin 33:300-11. 2012
  6. pmc Structure and activation of rhodopsin
    X Edward Zhou
    Laboratory of Structural Sciences, Van Andel Research Institute, NE, Grand Rapids, MI 49503, USA
    Acta Pharmacol Sin 33:291-9. 2012
  7. pmc Aberrantly elevated microRNA-34a in obesity attenuates hepatic responses to FGF19 by targeting a membrane coreceptor β-Klotho
    Ting Fu
    Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, IL 61801, USA
    Proc Natl Acad Sci U S A 109:16137-42. 2012
  8. pmc Structural basis for molecular recognition at serotonin receptors
    Chong Wang
    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Science 340:610-4. 2013
  9. pmc Structural features for functional selectivity at serotonin receptors
    Daniel Wacker
    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Science 340:615-9. 2013
  10. pmc Bile acid signal-induced phosphorylation of small heterodimer partner by protein kinase Cζ is critical for epigenomic regulation of liver metabolic genes
    Sunmi Seok
    Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    J Biol Chem 288:23252-63. 2013

Research Grants

  1. Spatio-temporal dynamics of GEF-GTPase networks
    KLAUS MICHAEL HAHN; Fiscal Year: 2013
  2. Interdisciplinary center of excellence for the study of pain and sensory function
    Ian D Meng; Fiscal Year: 2013
  3. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
  4. Contraception by Blockade of Periovulatory Events in Primates
    Richard L Stouffer; Fiscal Year: 2013
  5. Structures of Protein Complexes Regulating Transcription in Enbryonic Stem Cells
    Robert J Fletterick; Fiscal Year: 2013
  6. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
  7. Hepatic Lipid Mobilization by Nuclear Hormone Receptors
    Yoon Kwang Lee; Fiscal Year: 2013
  8. Center for Reproductive Science and Medicine
    Pamela L Mellon; Fiscal Year: 2013
  9. EINSTEIN AGING STUDY
    Richard B Lipton; Fiscal Year: 2013
  10. Chemistry and Biology of Coagulation
    Sriram Krishnaswamy; Fiscal Year: 2013

Detail Information

Publications33

  1. pmc A mechanistic basis for converting a receptor tyrosine kinase agonist to an antagonist
    W David Tolbert
    Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, Grand Rapids, MI 49503, USA
    Proc Natl Acad Sci U S A 104:14592-7. 2007
    ..This strategy of antagonist design may be applicable for other growth factor receptors by selectively abolishing the receptor activation ability but not the receptor binding of the growth factors...
  2. pmc Identification of a lysosomal pathway that modulates glucocorticoid signaling and the inflammatory response
    Yuanzheng He
    Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue Northeast, Grand Rapids, MI 49503, USA
    Sci Signal 4:ra44. 2011
    ..Thus, we showed that glucocorticoid signaling is regulated by lysosomes, which provides a mechanistic basis for treating inflammation and autoimmune diseases with a combination of glucocorticoids and lysosomal inhibitors...
  3. pmc Identification and mechanism of 10-carbon fatty acid as modulating ligand of peroxisome proliferator-activated receptors
    Raghu R V Malapaka
    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503, USA
    J Biol Chem 287:183-95. 2012
    ..Together, these results suggest that DA is a modulating ligand for PPARs, and the structure can aid in designing better and safer PPARγ-based drugs...
  4. pmc Structural conservation of ligand binding reveals a bile acid-like signaling pathway in nematodes
    Xiaoyong Zhi
    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
    J Biol Chem 287:4894-903. 2012
    ....
  5. pmc Structure and mechanism for recognition of peptide hormones by Class B G-protein-coupled receptors
    Kuntal Pal
    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503, USA
    Acta Pharmacol Sin 33:300-11. 2012
    ..This review summarizes the general structural principles that guide hormone binding by Class B ECDs and their implications in the design of peptide hormone analogs for therapeutic purposes...
  6. pmc Structure and activation of rhodopsin
    X Edward Zhou
    Laboratory of Structural Sciences, Van Andel Research Institute, NE, Grand Rapids, MI 49503, USA
    Acta Pharmacol Sin 33:291-9. 2012
    ..This review summarizes the structural features, the photoactivation, and the G protein signal transduction of rhodopsin...
  7. pmc Aberrantly elevated microRNA-34a in obesity attenuates hepatic responses to FGF19 by targeting a membrane coreceptor β-Klotho
    Ting Fu
    Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, IL 61801, USA
    Proc Natl Acad Sci U S A 109:16137-42. 2012
    ..The miR-34a/βKL/FGF19 axis may present unique therapeutic targets for FGF19-related human diseases, including metabolic disorders and cancer...
  8. pmc Structural basis for molecular recognition at serotonin receptors
    Chong Wang
    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Science 340:610-4. 2013
    ..Together with docking and mutagenesis studies, these structures provide a comprehensive structural basis for understanding receptor-ligand interactions and designing subtype-selective serotonergic drugs...
  9. pmc Structural features for functional selectivity at serotonin receptors
    Daniel Wacker
    Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Science 340:615-9. 2013
    ..Given the relatively poor understanding of GPCR structure and function to date, insight into different GPCR signaling pathways is important to better understand both adverse and favorable therapeutic activities...
  10. pmc Bile acid signal-induced phosphorylation of small heterodimer partner by protein kinase Cζ is critical for epigenomic regulation of liver metabolic genes
    Sunmi Seok
    Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    J Biol Chem 288:23252-63. 2013
    ..This study identifies PKCζ as a novel key upstream regulator of BA-regulated SHP function, revealing the role of Thr-55 phosphorylation in epigenomic regulation of liver metabolism. ..
  11. ncbi Structural basis for molecular recognition of folic acid by folate receptors
    Chen Chen
    Program for Structural Biology and Drug Discovery, Van Andel Research Institute, 333 Bostwick Avenue North East, Grand Rapids, Michigan 49503, USA
    Nature 500:486-9. 2013
    ..The extensive interactions between the receptor and ligand readily explain the high folate-binding affinity of folate receptors and provide a template for designing more specific drugs targeting the folate receptor system. ..
  12. pmc The crystal structure of the orphan nuclear receptor NR2E3/PNR ligand binding domain reveals a dimeric auto-repressed conformation
    M H Eileen Tan
    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan, United States of America Department of Obstetrics and Gynecology, National University Hospital, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
    PLoS ONE 8:e74359. 2013
    ....
  13. ncbi Structural basis for RNA recognition by a dimeric PPR-protein complex
    Jiyuan Ke
    1 Laboratory of Structural Sciences, Center for Structural Biology and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan, USA 2
    Nat Struct Mol Biol 20:1377-82. 2013
    ..Together, these results establish a new model of RNA recognition by RNA-induced formation of an asymmetric dimer of a PPR protein. ..
  14. pmc Structure and function of Norrin in assembly and activation of a Frizzled 4-Lrp5/6 complex
    Jiyuan Ke
    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
    Genes Dev 27:2305-19. 2013
    ..These results provide crucial insights into the assembly and activation of the Norrin-Fz4-Lrp5/6 signaling complex. ..
  15. pmc PGC-1 coactivator activity is required for murine erythropoiesis
    Shuaiying Cui
    Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, Michigan, USA
    Mol Cell Biol 34:1956-65. 2014
    ....
  16. pmc The orphan nuclear receptor TR4 is a vitamin A-activated nuclear receptor
    X Edward Zhou
    Laboratory of Structural Sciences and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
    J Biol Chem 286:2877-85. 2011
    ..These findings demonstrate that TR4 is a ligand-regulated nuclear receptor and suggest that retinoids might have a much wider regulatory role via activation of orphan receptors such as TR4...
  17. pmc Thirsty plants and beyond: structural mechanisms of abscisic acid perception and signaling
    Karsten Melcher
    Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Ave N E, Grand Rapids, MI 49503, USA
    Curr Opin Struct Biol 20:722-9. 2010
    ....
  18. pmc Identification and mechanism of ABA receptor antagonism
    Karsten Melcher
    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan, USA
    Nat Struct Mol Biol 17:1102-8. 2010
    ..Together, our results establish a new concept of ABA receptor antagonism, illustrate its underlying mechanisms and provide a rational framework for discovering novel ABA receptor ligands...
  19. pmc Doubling the size of the glucocorticoid receptor ligand binding pocket by deacylcortivazol
    Kelly Suino-Powell
    Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, Grand Rapids, MI 49503, USA
    Mol Cell Biol 28:1915-23. 2008
    ....
  20. pmc Molecular recognition of parathyroid hormone by its G protein-coupled receptor
    Augen A Pioszak
    Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, N E, Grand Rapids, MI 49503, USA
    Proc Natl Acad Sci U S A 105:5034-9. 2008
    ..Our findings reveal critical insights into PTH actions and provide a rational template for drug design that targets this hormone signaling pathway...
  21. pmc Structural and biochemical basis for the binding selectivity of peroxisome proliferator-activated receptor gamma to PGC-1alpha
    Yong Li
    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
    J Biol Chem 283:19132-9. 2008
    ..These results provide a molecular basis for specific recruitment and functional interplay between PPARgamma and PGC-1alpha in glucose homeostasis and adipocyte differentiation...
  22. pmc Molecular recognition of nitrated fatty acids by PPAR gamma
    Yong Li
    Department of Pharmaceutical Sciences, Center for Pharmacogenetics, 709 Salk Hall, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
    Nat Struct Mol Biol 15:865-7. 2008
    ..Structural and functional studies of receptor-ligand interactions reveal the molecular basis of PPAR gamma discrimination of various naturally occurring fatty acid derivatives...
  23. pmc Identification of COUP-TFII orphan nuclear receptor as a retinoic acid-activated receptor
    Schoen W Kruse
    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan, USA
    PLoS Biol 6:e227. 2008
    ....
  24. pmc Molecular recognition of corticotropin-releasing factor by its G-protein-coupled receptor CRFR1
    Augen A Pioszak
    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
    J Biol Chem 283:32900-12. 2008
    ..These structural studies provide a molecular framework for understanding peptide binding and specificity by the CRF receptors as well as a template for designing potent and selective CRFR1 antagonists for therapeutic applications...
  25. pmc Bile acid signaling pathways increase stability of Small Heterodimer Partner (SHP) by inhibiting ubiquitin-proteasomal degradation
    Ji Miao
    Department of Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, Illinois 61801, USA
    Genes Dev 23:986-96. 2009
    ..These results demonstrate an important role for regulation of SHP stability in bile acid signaling in normal conditions, and that abnormal stabilization of SHP may be associated with metabolic disorders, including obesity and diabetes...
  26. pmc Identification of the nuclear receptor DAF-12 as a therapeutic target in parasitic nematodes
    Zhu Wang
    Department of Pharmacology and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
    Proc Natl Acad Sci U S A 106:9138-43. 2009
    ..stercoralis DAF-12 ligand-binding domain cocrystallized with dafachronic acids. These results reveal the molecular basis for DAF-12 ligand binding and identify nuclear receptors as unique therapeutic targets in parasitic nematodes...
  27. pmc Structural basis for parathyroid hormone-related protein binding to the parathyroid hormone receptor and design of conformation-selective peptides
    Augen A Pioszak
    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
    J Biol Chem 284:28382-91. 2009
    ..These results establish a molecular model for better understanding of how two biologically distinct ligands can act through a single receptor and provide a template for designing better PTH/PTHrP therapeutics...
  28. pmc A gate-latch-lock mechanism for hormone signalling by abscisic acid receptors
    Karsten Melcher
    Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, N E, Grand Rapids, Michigan 49503, USA
    Nature 462:602-8. 2009
    ..Together, our results identify a conserved gate-latch-lock mechanism underlying ABA signalling...
  29. pmc Expression, purification and primary crystallographic study of human androgen receptor in complex with DNA and coactivator motifs
    X Edward Zhou
    Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, NE Grand Rapids, MI 49503, USA
    Protein Expr Purif 71:21-7. 2010
    ..These results help establish a foundation for pursuing further crystallographic studies of an AR/DNA complex...
  30. pmc Identification of SRC3/AIB1 as a preferred coactivator for hormone-activated androgen receptor
    X Edward Zhou
    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
    J Biol Chem 285:9161-71. 2010
    ..These results provide a molecular mechanism for the selective utilization of SRC3 by hormone-activated AR, and they link the functional relationship between AR and SRC3 to the development and growth of prostate cancer...
  31. pmc Covalent peroxisome proliferator-activated receptor gamma adduction by nitro-fatty acids: selective ligand activity and anti-diabetic signaling actions
    Francisco J Schopfer
    Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA
    J Biol Chem 285:12321-33. 2010
    ..Administration of this class of signaling mediators to ob/ob mice revealed that NO(2)-FA lower insulin and glucose levels without inducing adverse side effects such as the increased weight gain induced by TZDs...
  32. pmc Structural basis for agonism and antagonism of hepatocyte growth factor
    W David Tolbert
    Laboratory of Structural Sciences, Van Andel Research Institute, 333 Bostwick Avenue, Grand Rapids, MI 49503, USA
    Proc Natl Acad Sci U S A 107:13264-9. 2010
    ..These results reveal the molecular determinants that regulate the agonist/antagonist properties of HGF NK2 and provide critical insights into the dimerization mechanism that regulates the Met receptor activation by HGF...
  33. pmc Structures and mechanism for the design of highly potent glucocorticoids
    Yuanzheng He
    Laboratory of Structural Sciences, Van Andel Research Institute, Grand Rapids, MI 49503, USA
    Cell Res 24:713-26. 2014
    ..Together, these results reveal key structural mechanisms of glucocorticoid potency and provide a rational basis for developing novel highly potent glucocorticoids. ..

Research Grants30

  1. Spatio-temporal dynamics of GEF-GTPase networks
    KLAUS MICHAEL HAHN; Fiscal Year: 2013
    ..abstract_text> ..
  2. Interdisciplinary center of excellence for the study of pain and sensory function
    Ian D Meng; Fiscal Year: 2013
    ..Completion of these Aims will develop the research careers of a multidisciplinary group of junior investigators, and establish the core facilities and equipment necessary to constitute a competitive research center. ..
  3. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
    ..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
  4. Contraception by Blockade of Periovulatory Events in Primates
    Richard L Stouffer; Fiscal Year: 2013
    ..abstract_text> ..
  5. Structures of Protein Complexes Regulating Transcription in Enbryonic Stem Cells
    Robert J Fletterick; Fiscal Year: 2013
    ..The accumulated structural and functional data would be immediately available to biochemical and clinical researchers, and therefore, would have a major impact on stem cell research as well as regenerative medicine. ..
  6. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
    ....
  7. Hepatic Lipid Mobilization by Nuclear Hormone Receptors
    Yoon Kwang Lee; Fiscal Year: 2013
    ....
  8. Center for Reproductive Science and Medicine
    Pamela L Mellon; Fiscal Year: 2013
    ..The SCCPIR Human Ovary Tissue Bank provides tissue to NIH-funded investigators nation-wide. ..
  9. EINSTEIN AGING STUDY
    Richard B Lipton; Fiscal Year: 2013
    ..Together, these Projects will help disentangle the multifactorial processes that lead to cognitive and locomotor decline and dementia. ..
  10. Chemistry and Biology of Coagulation
    Sriram Krishnaswamy; Fiscal Year: 2013
    ..This program seeks to develop new information by which key reactions of blood clotting are regulated. This information will lead to new concepts and strategies for the treatment of blood clotting-related human disease. ..
  11. Spatial and Temporal Regulation of Angiogenesis
    HAROLD FISHER DVORAK; Fiscal Year: 2013
    ..abstract_text> ..
  12. LRH-1: Structure-based Approach to Drug Design for Gastrointestinal Tumors
    James Bayrer; Fiscal Year: 2013
    ..abstract_text> ..
  13. Pacific Southwest RCE for Biodefense &Emerging Infectious Diseases Research
    Alan G Barbour; Fiscal Year: 2013
    ..abstract_text> ..
  14. EFFECT OF APOLIPOPROTEIN STRUCTURAL ADAPTABILITY
    ROBERT O apos MARA RYAN; Fiscal Year: 2013
    ....
  15. Molecular and Clinical Pharmacology of Retinopathy of Prematurity
    Jacob V Aranda; Fiscal Year: 2013
    ..The NYPD-PRC will surely elevate the level of scientific inquiry on molecular and clinical pharmacology of ROP to hasten its prevention and avert life-long blindness. ..
  16. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..