Cellular Retinoic Acid Binding Proteins: Functional Studies

Summary

Principal Investigator: Lorraine J Gudas
Abstract: DESCRIPTION (provided by applicant): Alterations in the expression of the genes that control stem cell differentiation and self-renewal often contribute to tumorigenesis. Our laboratory has studied the mechanisms by which retinoids (vitamin A (retinol) and its derivatives and metabolites), control gene expression in both normal stem cells and in tumors. Over this past grant period we have developed evidence that: a) the polycomb group (PcG) protein(s) play a major role in repressing retinoid signaling in embryonic stem (ES) cells;b) these polycomb mediated inhibitory signals are altered in tumor cells;and c) specific retinoid receptors act in concert with transcriptional coactivators in a gene specific context. Our immediate goal in the next grant period is to delineate the mechanisms by which the polycomb group mediated transcriptional repressive pathways and the retinoid transcriptional signaling pathways intersect. Our Specific Aims for the next grant period: 1) We will elucidate the mechanisms by which the polycomb proteins inhibit retinoid transcriptional activation and retinoic acid induced cell differentiation. This will be accomplished by a combination of ChIP (chromatin immunoprecipitation) assays;overexpression or reduced expression of key transcriptional regulatory proteins such as pCIP (SRC3), EZH2, SUZ12, and JMJD3 in F9 and ES Wt and RAR1, 2, and 3 null cells;and deletion of DNA regulatory elements such as the Hoxa1 RARE, followed by analysis of PcG protein binding. We also propose a comparison of 3T3 cells with H-Ras transformed 3T3 cells to assess how an oncogenic protein perturbs retinoid signaling. 2) We plan to define the domains of the specific retinoic acid receptors (RARs) 1, 2, and 3 (i.e. the receptors for all-trans retinoic acid (RA) and other retinoids) and the coactivators for these receptors that control the transcriptional events which result in cell differentiation (and, thus, aid in inhibiting tumor cell proliferation). 3) Finally, as part of our goal of understanding retinoid regulation of stem cell differentiation, we will undertake a genome-wide search for primary target genes of the RARs through the use of ChIP-on-chip (tiling) arrays or ChIP-seq technology. This approach will allow us to obtain key information about the genes transcriptionally activated as ES cells differentiate along different pathways. For these proposed experiments we will utilize (a) murine ES and teratocarcinoma stem cell lines with both alleles of each of the individual RARs "knocked out" by homologous recombination;(b) ES cell lines with some of the "downstream" RAR target genes "knocked out";and (c) mice that have each of the individual RARs knocked out by homologous recombination. This proposed research will increase our knowledge of the molecular mechanisms by which signaling by retinoids is accomplished, provide new knowledge that will be useful for improvement of 'differentiation therapy'for cancer, delineate the mechanisms by which retinoids signal so that we will understand why some tumors are resistant to retinoid therapy, and allow us to manipulate the expression or function of polycomb repressive proteins to increase the effectiveness of retinoid based therapies and differentiation strategies for stem cells.
Funding Period: 1987-07-15 - 2015-05-31
more information: NIH RePORT

Top Publications

  1. ncbi The putative human stem cell marker, Rex-1 (Zfp42): structural classification and expression in normal human epithelial and carcinoma cell cultures
    Nigel P Mongan
    Department of Pharmacology, Weill Medical College, Cornell University, New York, New York 10021, USA
    Mol Carcinog 45:887-900. 2006
  2. pmc Epigenomic reorganization of the clustered Hox genes in embryonic stem cells induced by retinoic acid
    Vasundhra Kashyap
    Department of Pharmacology, Weill Cornell Medical College, New York, New York 10065, USA
    J Biol Chem 286:3250-60. 2011
  3. pmc Role of androgen receptor and associated lysine-demethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer
    Eric C Kauffman
    Department of Urology, Weill Cornell Medical College, New York, New York 10065, USA
    Mol Carcinog 50:931-44. 2011
  4. pmc Rex1 (Zfp42) null mice show impaired testicular function, abnormal testis morphology, and aberrant gene expression
    Naira C Rezende
    Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
    Dev Biol 356:370-82. 2011
  5. pmc Emerging roles for retinoids in regeneration and differentiation in normal and disease states
    Lorraine J Gudas
    PharmacologyDepartment, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
    Biochim Biophys Acta 1821:213-21. 2012
  6. pmc Epigenetic regulation by RARα maintains ligand-independent transcriptional activity
    Kristian B Laursen
    Pharmacology Department of Weill Cornell Medical College of Cornell University, NY 10065, USA
    Nucleic Acids Res 40:102-15. 2012
  7. pmc Polycomb repressive complex 2 impedes intestinal cell terminal differentiation
    Yannick D Benoit
    CIHR Team on the Digestive Epithelium, Département d Anatomie et Biologie Cellulaire, Faculte de Medecine et des Sciences de la Sante, Universite de Sherbrooke, Sherbrooke, QC, Canada
    J Cell Sci 125:3454-63. 2012
  8. pmc Inhibition of PRC2 histone methyltransferase activity increases TRAIL-mediated apoptosis sensitivity in human colon cancer cells
    Yannick D Benoit
    Department of Pharmacology, Weill Cornell Medical College, New York, New York 10065, USA
    J Cell Physiol 228:764-72. 2013
  9. pmc RARγ is essential for retinoic acid induced chromatin remodeling and transcriptional activation in embryonic stem cells
    Vasundhra Kashyap
    Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
    J Cell Sci 126:999-1008. 2013
  10. pmc The lysine specific demethylase-1 (LSD1/KDM1A) regulates VEGF-A expression in prostate cancer
    Vasundhra Kashyap
    Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA
    Mol Oncol 7:555-66. 2013

Detail Information

Publications34

  1. ncbi The putative human stem cell marker, Rex-1 (Zfp42): structural classification and expression in normal human epithelial and carcinoma cell cultures
    Nigel P Mongan
    Department of Pharmacology, Weill Medical College, Cornell University, New York, New York 10021, USA
    Mol Carcinog 45:887-900. 2006
    ....
  2. pmc Epigenomic reorganization of the clustered Hox genes in embryonic stem cells induced by retinoic acid
    Vasundhra Kashyap
    Department of Pharmacology, Weill Cornell Medical College, New York, New York 10065, USA
    J Biol Chem 286:3250-60. 2011
    ..Highly coordinated, long range epigenetic Hox cluster reorganization is closely linked to transcriptional activation and is triggered by RARγ located at the Hoxa1 3'-RA-responsive element...
  3. pmc Role of androgen receptor and associated lysine-demethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer
    Eric C Kauffman
    Department of Urology, Weill Cornell Medical College, New York, New York 10065, USA
    Mol Carcinog 50:931-44. 2011
    ....
  4. pmc Rex1 (Zfp42) null mice show impaired testicular function, abnormal testis morphology, and aberrant gene expression
    Naira C Rezende
    Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
    Dev Biol 356:370-82. 2011
    ..We report a distinct cellular localization of total STAT3 protein in Rex1(-/-) affected testes. Our data suggest that loss of Rex1 leads to impaired testicular function...
  5. pmc Emerging roles for retinoids in regeneration and differentiation in normal and disease states
    Lorraine J Gudas
    PharmacologyDepartment, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
    Biochim Biophys Acta 1821:213-21. 2012
    ..This article is part of a Special Issue entitled Retinoid and Lipid Metabolism...
  6. pmc Epigenetic regulation by RARα maintains ligand-independent transcriptional activity
    Kristian B Laursen
    Pharmacology Department of Weill Cornell Medical College of Cornell University, NY 10065, USA
    Nucleic Acids Res 40:102-15. 2012
    ..We propose that RARα plays an important role in cellular memory and imprinting by regulating the CpG methylation status of specific promoter regions...
  7. pmc Polycomb repressive complex 2 impedes intestinal cell terminal differentiation
    Yannick D Benoit
    CIHR Team on the Digestive Epithelium, Département d Anatomie et Biologie Cellulaire, Faculte de Medecine et des Sciences de la Sante, Universite de Sherbrooke, Sherbrooke, QC, Canada
    J Cell Sci 125:3454-63. 2012
    ....
  8. pmc Inhibition of PRC2 histone methyltransferase activity increases TRAIL-mediated apoptosis sensitivity in human colon cancer cells
    Yannick D Benoit
    Department of Pharmacology, Weill Cornell Medical College, New York, New York 10065, USA
    J Cell Physiol 228:764-72. 2013
    ....
  9. pmc RARγ is essential for retinoic acid induced chromatin remodeling and transcriptional activation in embryonic stem cells
    Vasundhra Kashyap
    Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
    J Cell Sci 126:999-1008. 2013
    ..Our data show major epigenetic changes associated with addition of the RARγ agonist RA in ES cells...
  10. pmc The lysine specific demethylase-1 (LSD1/KDM1A) regulates VEGF-A expression in prostate cancer
    Vasundhra Kashyap
    Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA
    Mol Oncol 7:555-66. 2013
    ..New therapies targeting LSD1 activity should be useful in the treatment of hormone dependent and independent prostate cancer...
  11. pmc CDK1 interacts with RARγ and plays an important role in treatment response of acute myeloid leukemia
    Andreas Hedblom
    Department of Laboratory Medicine, Division of Experimental Cancer Research, Clinical Research Center, Lund University, Malmo, Sweden
    Cell Cycle 12:1251-66. 2013
    ..Our study reveals a novel mechanism by which CDK1 and RARγ coordinate with ATRA to influence cell cycle progression and cellular differentiation...
  12. pmc Pharmacological inhibition of polycomb repressive complex-2 activity induces apoptosis in human colon cancer stem cells
    Yannick D Benoit
    Pharmacology Department, Weill Cornell Medical College, NY 10065, USA
    Exp Cell Res 319:1463-70. 2013
    ..Taken together, our findings suggest that pharmacological inhibition of PRC2 histone methyltransferase activity may constitute a new, epigenetic therapeutic strategy to target highly tumorigenic and metastatic colon cancer stem cells...
  13. pmc Polycomb recruitment attenuates retinoic acid-induced transcription of the bivalent NR2F1 gene
    Kristian B Laursen
    Department of Pharmacology, Weill Cornell Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA
    Nucleic Acids Res 41:6430-43. 2013
    ..We propose that PRC2 recruitment attenuates the RA-associated transcriptional activation of a subset of genes. Such a mechanism would permit the fine-tuning of transcriptional networks during differentiation. ..
  14. pmc Deletion of retinoic acid receptor β (RARβ) impairs pancreatic endocrine differentiation
    Ronald J Pérez
    Pharmacology Department, Weill Medical College of Cornell University, New York, NY 10065, USA
    Exp Cell Res 319:2196-204. 2013
    ..We conclude that RARβ activity is essential for proper differentiation of ES cells to pancreatic endocrine cells. ..
  15. pmc Cytochrome p450 cyp26a1 alters spinal motor neuron subtype identity in differentiating embryonic stem cells
    Megan J Ricard
    From the Departments of Pharmacology and
    J Biol Chem 288:28801-13. 2013
    ..Our data suggest a strategy for increasing LMC-type MNs from ESCs by blocking Cyp26a1 in cell replacement/ESC differentiation therapy to treat neurodegenerative diseases, such as amyotrophic lateral sclerosis. ..
  16. pmc Retinoids induce stem cell differentiation via epigenetic changes
    Lorraine J Gudas
    Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA Department of Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA Electronic address
    Semin Cell Dev Biol 24:701-5. 2013
    ..A more complete understanding of retinoid-dependent stem cell differentiation should reward us with new insights into the failure to maintain a differentiated state that is an essential part of neoplastic cell transformation and cancer...
  17. ncbi Retinoids, retinoic acid receptors, and cancer
    Xiao Han Tang
    Department of Pharmacology, Weill Cornell Medical College, New York, New York 10065, USA
    Annu Rev Pathol 6:345-64. 2011
    ..Thus, retinoid research benefits both cancer prevention and cancer treatment...
  18. pmc RARγ is required for correct deposition and removal of Suz12 and H2A.Z in embryonic stem cells
    Ramon Amat
    Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, New York 10065, USA
    J Cell Physiol 226:293-8. 2011
    ..Addition of RA causes removal of H2A.Z and Suz12 from RARγ target genes when the genes are transcriptionally activated...
  19. pmc Retinoid regulated association of transcriptional co-regulators and the polycomb group protein SUZ12 with the retinoic acid response elements of Hoxa1, RARbeta(2), and Cyp26A1 in F9 embryonal carcinoma cells
    Robert F Gillespie
    Molecular Biology Program of Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10021, USA
    J Mol Biol 372:298-316. 2007
    ..These studies provide insight into the dynamics of association of co-regulators with RAREs and demonstrate a novel link between RA signaling and PcG repression...
  20. ncbi Overexpression of CRABPI in suprabasal keratinocytes enhances the proliferation of epidermal basal keratinocytes in mouse skin topically treated with all-trans retinoic acid
    Xiao Han Tang
    Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10021, USA
    Exp Cell Res 314:38-51. 2008
    ....
  21. ncbi Retinoic acid receptor isotype specificity in F9 teratocarcinoma stem cells results from the differential recruitment of coregulators to retinoic response elements
    Robert F Gillespie
    Molecular Biology Program, Weill Graduate School of Medical Sciences, Cornell University, New York, New York 10021, USA
    J Biol Chem 282:33421-34. 2007
    ..Thus, transcriptional components of the RAR signaling pathway are specifically required for displacement of SUZ12 from RAREs during RA-mediated differentiation of F9 cells...
  22. pmc LIF removal increases CRABPI and CRABPII transcripts in embryonic stem cells cultured in retinol or 4-oxoretinol
    Michelle A Lane
    Department of Human Ecology, Division of Nutritional Sciences, The University of Texas at Austin, GEA 117, A2700 Austin, TX 78712, USA
    Mol Cell Endocrinol 280:63-74. 2008
    ..The enormous increases in CRABPI and II transcripts ( approximately 60 and 400-fold, respectively) in the absence of LIF may regulate aspects of the ES cell differentiation program in response to retinol...
  23. pmc Gene expression profiling elucidates a specific role for RARgamma in the retinoic acid-induced differentiation of F9 teratocarcinoma stem cells
    Dan Su
    Department of Pharmacology, Weill Cornell Medical College United States
    Biochem Pharmacol 75:1129-60. 2008
    ..Several genes in the Wnt signaling pathway were regulated by RARgamma. Delineation of the receptor-specific actions of RA with respect to cell proliferation and differentiation should result in more effective therapies with this drug...
  24. ncbi Overexpression of COUP-TF1 in murine embryonic stem cells reduces retinoic acid-associated growth arrest and increases extraembryonic endoderm gene expression
    Yong Zhuang
    Department of Pharmacology, Weill Medical College of Cornell University, Room E 409, 1300 York Ave, New York, NY 10021, USA
    Differentiation 76:760-71. 2008
    ..Our results revealed for the first time that COUP-TF1 is an important signaling molecule during vitamin A (Rol)-mediated very early stage of embryonic development...
  25. pmc Transcriptional activation of the suppressor of cytokine signaling-3 (SOCS-3) gene via STAT3 is increased in F9 REX1 (ZFP-42) knockout teratocarcinoma stem cells relative to wild-type cells
    Juliana Xu
    Pharmacology Department, Weill Cornell Medical College, 1300 York Avenue, Room E 409, New York, NY 10021, USA
    J Mol Biol 377:28-46. 2008
    ..Thus, Rex1, which is highly expressed in stem cells, inhibits signaling via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, thereby modulating the differentiation of F9 cells...
  26. ncbi CYP26A1 knockout embryonic stem cells exhibit reduced differentiation and growth arrest in response to retinoic acid
    Simne Langton
    Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, Rm E 409, New York, NY 10021, USA
    Dev Biol 315:331-54. 2008
    ..Collectively, our results show that CYP26A1 activity regulates intracellular RA levels, cell proliferation, transcriptional regulation of primary RA target genes, and ES cell differentiation to parietal endoderm...
  27. ncbi Retinoic acid receptor gamma activates receptor tyrosine kinase Tie1 gene transcription through transcription factor GATA4 in F9 stem cells
    Dan Su
    Department of Pharmacology, Weill Cornell Medical College, New York NY 10065, USA
    Exp Hematol 36:624-41. 2008
    ..Our goal was to analyze the Tie1 gene, which encodes a surface receptor tyrosine kinase expressed in the hematovascular system...
  28. pmc The truncated Hoxa1 protein interacts with Hoxa1 and Pbx1 in stem cells
    Cristina C Fernandez
    Department of Pharmacology, Weill Cornell Medical College, 1300 York Avenue, New York, New York 10065, USA
    J Cell Biochem 106:427-43. 2009
    ..However, the F9-399 line exhibits no differences in RA-induced proliferation arrest or endogenous Hoxb1, Pbx1, Hoxa5, Cyp26a1, GATA4, or Meis mRNA levels when compared to F9 wild-type...
  29. pmc Retinol saturase promotes adipogenesis and is downregulated in obesity
    Michael Schupp
    Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, and The Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA
    Proc Natl Acad Sci U S A 106:1105-10. 2009
    ..Thus, RetSat plays an important role in the biology of adipocytes, where it favors normal differentiation, yet is reduced in the obese state. RetSat is thus a novel target for therapeutic intervention in metabolic disease...
  30. pmc Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the NANOG, OCT4, and SOX2 pluripotency transcription factors with polycomb repressive complexes and stem cell microRNAs
    Vasundhra Kashyap
    Department of Pharmacology, Graduate Programs in Pharmacology, Weill Cornell Medical College, New York, New York 10065, USA
    Stem Cells Dev 18:1093-108. 2009
    ....
  31. pmc Analysis of Rex1 (zfp42) function in embryonic stem cell differentiation
    Kymora B Scotland
    Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 10065, USA
    Dev Dyn 238:1863-77. 2009
    ..These data, taken together, suggest that Rex1 influences differentiation, cell cycle regulation, and cancer progression...
  32. pmc Epigenetic regulatory mechanisms distinguish retinoic acid-mediated transcriptional responses in stem cells and fibroblasts
    Vasundhra Kashyap
    Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, New York 10065, USA
    J Biol Chem 285:14534-48. 2010
    ..We have delineated the complex mechanisms that control RA-mediated transcription in fibroblasts versus stem cells...
  33. pmc Retinoids regulate stem cell differentiation
    Lorraine J Gudas
    Department of Pharmacology, Weill Cornell Medical College of Cornell University, New York, New York 10065, USA
    J Cell Physiol 226:322-30. 2011
    ..Mechanistic studies of retinoid signaling continue to suggest novel drug targets and will improve therapeutic strategies for cancer and other diseases, such as immune-mediated inflammatory diseases...
  34. pmc Retinoid receptor signaling and autophagy in acute promyelocytic leukemia
    Nina Orfali
    Cork Cancer Research Center, University College Cork, Cork, Ireland Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA
    Exp Cell Res 324:1-12. 2014
    ..Here we discuss retinoid signaling in hematopoiesis, leukemogenesis, and APL treatment. We highlight autophagy as a potential important regulator in anti-leukemic strategies. ..

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. ENDOGENOUS NITRITE CARCINOGENESIS IN MAN
    Steven R Tannenbaum; Fiscal Year: 2013
    ..This Program has already demonstrated that NO-synthase inhibitors can ameliorate the early stages of tissue changes in IBD and colon cancer in our animal models. ..
  3. Wisconsin Center of Excellence in Genomics Science
    Michael Olivier; Fiscal Year: 2013
    ..Data, technology, and software will be widely disseminated by multiple mechanisms including licensing and commercialization activities. ..
  4. Center on the Microenvironment and Metastasis
    Michael L Shuler; Fiscal Year: 2013
    ..By this approach the impact of this research should be felt far more widely than ordinary individual investigator projects. ..
  5. The MIT Center for Single-Cell Dynamics in Cancer (SCDC)
    Scott R Manalis; Fiscal Year: 2013
    ..These facilities and all reagents generated by the cores will be made available to other PS-OCs. ..
  6. University of Maryland Greenebaum Cancer Center Support Grant
    Kevin J Cullen; Fiscal Year: 2013
    ..Reflecting our remarkable and continued growth, UMGCC seeks to renew its CCSG to enhance and expand its efforts in high-quality and clinically relevant cancer research. ..
  7. THERAPY OF LYMPHOMA/LEUKEMIA WITH MONOCLONAL ANTIBODIES
    Oliver W Press; Fiscal Year: 2013
    ..We anticipate that the investigations described in this application will allow us to maximize the therapeutic efficacy and minimize the toxicity of myeloablative RIT for hematologic malignancies. ..
  8. Longitudinal Epigenomic Tracking of the Reprogramming Process
    Michael P Snyder; Fiscal Year: 2013
    ..By understanding the epigenomic landscapes of different tissues and ages and tracking changes during reprogramming, we hope to identify even more features associated with successful and abortive de-differentiation. ..
  9. Molecular and Architectural Mechanisms of Reprogramming to Pluripotency
    Kathrin Plath; Fiscal Year: 2013
    ..The plan provides unique experimental synergies that address the objectives of the funding announcement. ..
  10. Center for the Study of Reproductive Biology and Women's Health
    Jeffrey W Pollard; Fiscal Year: 2013
    ..He holds several senior administrative appointments in the College of Medicine and is well able to administer the proposed SCCPIR internally and to enable effective interactions with other SCCPIRs. ..
  11. The role of the nucleoporin Nup98 in gene regulation
    Martin W Hetzer; Fiscal Year: 2013
    ..These approaches have the potential to reveal the gene regulatory role of mammalian Nup98 and provide insight into its leukemia-causing potential. ..
  12. Role of 11q23 Chromosome Abnormalities in the Causation of Acute Leukemia
    Carlo M Croce; Fiscal Year: 2013
    ..abstract_text> ..
  13. Role of the Histone Modifier KDM6A in Stem Cell Differentiation
    Min Gyu Lee; Fiscal Year: 2013
    ....
  14. Diet and Alcohol Induced Epigenetic Changes in Oral Cavity Carcinogenesis Model
    Lorraine J Gudas; Fiscal Year: 2013
    ....
  15. Mechanistic Pharmacology of Anti-Mitotics and Apoptosis Regulation
    Timothy J Mitchison; Fiscal Year: 2013
    ..In aim 4 we will pursue several approaches towards translating mechanistic understanding from aims 1-3 into improved patient care. ..
  16. Alcohol-Induced Epigenetic Changes in Stem Cells
    Lorraine J Gudas; Fiscal Year: 2013
    ..Moreover, unlike genetic mutations that change the DNA sequence and are generally permanent, epigenetic changes can be reversed and therefore are reasonable targets for therapies to treat alcohol-induced tissue injury. ..
  17. 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. ..
  18. CANCER CENTER SUPPORT GRANT
    Nancy E Davidson; Fiscal Year: 2013
    ..abstract_text> ..