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Program Director/Principal Investigator (Last, First, Middle): BIOGRAPHICAL SKETCH Provide the following information for the Senior/key personnel and other significant contributors in the order listed on Form Page 2. Follow this format for each person. DO NOT EXCEED FOUR PAGES. NAME POSITION TITLE Faraday, Nauder Associate Professor, Anesthesiology/CCM eRA COMMONS USER NAME (credential, e.g., agency login) nfarada1 EDUCATION/TRAINING (Begin with baccalaureate or other initial professional education, such as nursing, include postdoctoral training and residency training if applicable.) DEGREE INSTITUTION AND LOCATION MM/YY FIELD OF STUDY (if applicable) Columbia University, New York, NY Mount Sinai School of Medicine, New York, NY Johns Hopkins University, Baltimore, MD Johns Hopkins University, Baltimore, MD Johns Hopkins University, Baltimore, MD Johns Hopkins University, Baltimore, MD BA MD residency fellowship Postdoc MPH 5/84 5/88 88-92 92-93 93-96 5/11 Biology/Psychology Medicine Anesthesiology Critical Care Medicine Platelet biology Epidemiology/Health Policy A. Personal Statement Over the past 15 years I have served as the PI or Co-PI on several studies aimed at identifying mechanisms for heightened platelet reactivity and diminished response to anti-platelet therapy. This work has involved a variety of techniques including: in vitro platelet function studies, mouse models of platelet-mediated clot formation, and genetic analyses. I have been collaborating with Drs. Lew and Diane Becker on the GeneSTAR study since its inception, providing expertise in platelet biology and laboratory analyses of platelet phenotype. B. Position and Honors 1988 Alpha Omega Alpha Medical Honor Society 1988 Upjohn Award for Clinical Excellence 1993-2001 Assistant Professor, Department of Anesthesiology/CCM, Johns Hopkins University, Baltimore, MD 1994-2004 Co-Director, Cardiac Surgical Intensive Care Unit, The Johns Hopkins Hospital, Baltimore, MD 1999-present Director, Perioperative Hemostasis and Thrombosis Research Laboratory, Johns Hopkins University, Baltimore, MD 2001-present Associate Professor, Department of Anesthesiology/CCM, Johns Hopkins University. Baltimore, MD 2003 Association of Cardiac Anesthesiologists induction 2004-present Director, Perioperative Genomic and Translational Research, Department of Anesthesiology/CCM, Johns Hopkins University. Baltimore, MD 2004 Association of University Anesthetists induction C. Selected Peer-reviewed Publications 1. Faraday N, Martinez EA, Scharpf RB, Kasch-Semenza L, Dorman T, Pronovost PJ, Perler B, Gerstenblith G, Bray PF, Fleisher LA. Platelet gene polymorphisms and cardiac risk assessment in vascular surgical patients. Anesthesiology: 101: 1291-7, 2004 2. Morrell C, Matsushita K, Chiles K, Scharpf R, Yamakuchi M, Simmons A, Mankowski JL, Baldwin W, Faraday N, Lowenstein C. Regulation of platelet granule exocytosis by S-nitrosylation. Proc Natl Acad Sci USA 102:3782-7, 2005 3. Becker DM, Segal J, Vaidya D, Yanek LR, Herrera-Galeano JE, Bray PF, Moy TF, Becker LC, Faraday N. Sex differences in platelet reactivity and response to low-dose aspirin therapy. JAMA 295: 1420-27, 2006. 4. Ferlito M, Irani K, Faraday N, Lowenstein CJ. Nitric oxide inhibits exocytosis of cytolytic granules from lymphokine-activated killer cells. Proc Natl Acad Sci USA 103: 11689-94, 2006. PHS 398/2590 (Rev. 06/09) Page Biographical Sketch Format Page Program Director/Principal Investigator (Last, First, Middle): 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. Faraday N, Becker DM, Yanek LR, Herrera-Galeano JE, Segal JB, Moy TF, Bray PF, Becker LC. Relation between atherosclerosis risk factors and aspirin resistance in a primary prevention population. Am J Cardiol 98: 774-9, 2006 Faraday N, Yanek LR, Mathias R, Herrera-Galeano JE, Vaidya D, Moy TF, Fallin MD, Wilson AF, Bray PF, Becker LC, Becker DM. Heritability of platelet responsiveness to aspirin in activation pathways directly and indirectly related to cyclooxygenase-1. Circulation 115: 2490-6, 2007. Bray PF, Mathias RA, Faraday N, Yanek LR, Fallin MD, Herrera-Galeano JE, Wilson AF, Becker LC, Becker DM. Heritability of platelet function in families with premature coronary artery disease. J Thromb Haemost 5:1617-23, 2007. Bordeaux B, Yanek LR, Moy TF, White LW, Becker LC, Faraday N, Becker DM. Casual chocolate consumption and inhibition of platelet function. Prev Cardiol Fall; 10(4): 175-80, 2007. Faraday N, Becker DM, Becker LC. Pharmacogenomics of platelet responsiveness to aspirin. Pharmacogenomics Oct. 8(10): 1413-25, 2007. Morrell CN, Sun H, Ikeda M, Beique JC, Swaim AM, Mason E, Martin TV, Thompson LE, Gozen O, Ampagoomian D, Sprengel R, Rothestein J, Faraday N, Huganir R, Lowenstein CJ. Glutamate mediates platelet activation through the AMPA receptor. J Exp Med. Mar 17;205(3):575-84 2008. Qayyum R, Becker DM, Yanek LR, Moy TF, Becker LC, Faraday N, Vaidya D. Platelet Inhibition by Aspirin 81 and 325 mg/day in Men Versus Women Without Clinically Apparent Cardiovascular Disease. Am J Cardiol 101: 1356-63, 2008. Herrera-Galeano JE, Becker DM, Wilson AF, Yanek LR, Bray P, Vaidya D, Faraday N, Becker LC. A Novel Variant in the Platelet Endothelial Aggregation Receptor-1 Gene Is Associated With Increased Platelet Aggregability. Arterioscler Thromb Vasc Biol 28 (8): 1484-90, 2008. Faraday N, Yanek LR, Vaidya D, Kral B, Qayyum R, Herrera-Galeano JE, Moy TF, Becker DM, Becker LC. Leukocyte Count is Associated with Increased Platelet Reactivity and Diminished Response to Aspirin in Healthy Individuals with a Family History of Coronary Artery Disease. Thromb Res 124: 311– 317, 2009. Blasco-Colmenares E, Perl TM, Guallar E, Baumgartner WA, Conte JV, Alejo D, Pastor-Barriuso R, Sharrett AR, Faraday N. Aspirin plus clopidogrel and risk of infection after coronary artery bypass surgery. Arch Intern Med 169: 788-96, 2009. Vaidya D, Yanek LR, Faraday N, Moy TF, Becker LC, Becker DM. Native Platelet Aggregation and Response to Aspirin in Persons with the Metabolic Syndrome and its Components. Metab Syndr Relat Disord 7(4):289-96, 2009. Sun H, Swaim A, Herrera JE, Becker D, Becker L, Srivastava K, Thompson LE, Shero MR, PerezTamayo A, Suktitpat B, Mathias R, Contractor A, Faraday N, Morrell CN. Platelet Kainate Receptor Signaling Promotes Thrombosis by Stimulating Cyclooxygenase Activation. Circ Res. 2009 Aug 13. Shuldiner AR, O’Connell JR, Bliden KP, Gandhi A, Ryan K, Horenstein RB, Damcott CM, Pakyz R, Tantry US, Gibson Q, Pollin TI, Post W, Parsa A, Mitchell BD, Faraday N, Herzog W, Gurbel PA. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA 302(8):849-858, 2009 Johnson AD, Yanek LR, Chen MH, Faraday N, Larson MG, Tofler G, Lin SJ, Kraja AT, Province MA, Yang Q, Becker DM, O'Donnell CJ, Becker LC. A combined genome-wide linkage and association approach to find susceptibility loci for platelet function phenotypes in European American and African American families with coronary artery disease. Nat Genet 42(7):608-13, 2010 Mathias RA, Kim Y, Sung H, Yanek LR, Mantese VJ, Hererra-Galeano JE, Ruczinski I, Wilson AF, Faraday N, Becker LC, Becker DM. A combined genome-wide linkage and association approach to find susceptibility loci for platelet function phenotypes in European American and African American families with coronary artery disease. BMC Med Genomics 3:22, 2010 Musunuru K, Post WS, Herzog W, Shen H, O'Connell JR, McArdle PF, Ryan KA, Gibson Q, Cheng YC, Clearfield E, Johnson AD, Tofler G, Yang Q, O'Donnell CJ, Becker DM, Yanek LR, Becker LC, Faraday N, Bielak LF, Peyser PA, Shuldiner AR, Mitchell BD. Association of single nucleotide polymorphisms on chromosome 9p21.3 with platelet reactivity: a potential mechanism for increased vascular disease. Circ Cardiovasc Genet 3:445-53, 2010 PHS 398/2590 (Rev. 06/09) Page Continuation Format Page Program Director/Principal Investigator (Last, First, Middle): 21. 22. 23. Vaidya D, Yanek LR, Herrera-Galeano JE, Mathias RA, Moy TF, Faraday N, Becker LC, Becker DM. A common variant in the Von Willebrand factor gene is associated with multiple functional consequences. Am J Hematol 85:971-3, 2010 Brown C, Joshi B, Faraday N, Shah A, Yuh D, Rade JJ, Hogue CW. Emergency cardiac surgery in patients with acute coronary syndromes: a review of the evidence and perioperative implications of medical and mechanical therapeutics. Anesth Analg 112(4):777-99, 2011. Faraday N, Yanek LR, Yang XP, Mathias R, Herrera-Galeano JE, Suktitipat B, Qayyum R, Johnson AD, Chen M-H, Tofler GH, Ruczinski I, Friedman AD, Gylfason A, Thorsteinsdottir U, Bray PF, O’Donnell CJ, Becker DM, Becker LC. Identification of a specific intronic PEAR1 gene variant associated with greater platelet aggregability and protein expression. Blood 118: 3367-3375, 2011 D. Research Support Ongoing Research Support RC1 HL099677-01 9/30/09-8/31/2011 NIH/NHLBI Title: Role of Neutrophil-Platelet Interactions in Vascular Occlusive Disorders The purpose of the proposed studies is to identify a key point in the communication between leukocytes and platelets that can serve as a target for novel pharmaceuticals that will prevent vascular occlusion despite vessel injury. We will examine the effects of neutrophil count and cathepsin G on vascular outcomes by manipulating neutrophil counts in vivo, using a specific pharmacologic inhibitor of cathepsin G, and using cathepsin G knockout mice. At the end of the 2-year study period we expect to demonstrate that: 1) neutrophilia promotes platelet activation and vascular occlusion in mouse models of bleeding time, arteriolar thrombosis, and stroke; 2) neutrophil cathepsin G is a critical molecular mediator of platelet accumulation and luminal occlusion at sites of vascular injury; and, 3) neutrophilia promotes resistance to the anti-platelet effects of aspirin in vivo but does not reduce the vaso-protective effects of cathepsin G inhibition. Role: Principal Investigator 9U01 HL105198-06 (PI: A Shuldiner) 9/30/10-9/29/15 NIH/NIGMS Pharmacogenomics of Anti-Platelet Interventions-2 (PAPI-2) The goal of this study is determine the efficacy of genetic testing to direct thienopyridene therapy in patients with acute coronary syndromes and after PCI and to identify rare variants that determine response to antiplatelet therapy. Role: Co-Investigator RFA-HL-11-006 (PI: L. Becker) 7/1/11-6/30/16 NIH/NHLBI Functional Genomics of Platelet Aggregation Using iPS and Derived Megakaryocytes In 3 phases, we will (1) create pluripotent stem cells (iPS) from peripheral blood mononuclear cells, and then differentiate these stem cells into megakaryocytes, (2) efficiently produce iPS and megakaryocytes using a novel pooling method, and (3) produce iPS and megakaryocytes from 400 subjects in GeneSTAR (200 whites, 200 African Americans), selected based on specific hypotheses derived from GWAS signals in native and post aspirin platelet function; characterize genetic mRNA transcripts using a comprehensive Affymetrix exon array; measure protein expression for transcripts of interest using mass spectrometry; examine mRNA and protein expression patterns for each GWAS signal to determine the functional pathway(s) involved in native platelet phenotypes; and examine the functional genomics of variations in responsiveness to aspirin using a prior genotyped and phenotyped population. Role: Co-Investigator P01HL107153 (PI: G Hart) 7/1/11-6/30/18 NIH/NHLBI Glycoconjugates and cardiovascular disease The main focus of this research is to apply emerging glycoproteomic and glycomic technologies in human platelets in order to identify the specific alterations in platelet glycoproteins and glycans that contribute to PHS 398/2590 (Rev. 06/09) Page Continuation Format Page Program Director/Principal Investigator (Last, First, Middle): heightened platelet reactivity and to use this information to design novel anti-thrombotic agents that target glycoproteins and complex sugars to treat cardiovascular disease. Role: Co-Investigator Project 4 Completed Research Support U01 GM074518 (PI: A. Shuldiner) 9/05-9/10 NIH/NIGMS Title: Pharmacogenomics of anti-platelet agents for CVD prevention This project seeks to determine the genetic underpinnings of the inter-individual variability of clopidogrel and aspirin response in 1000 Old Order Amish subjects from very large extended pedigrees. Platelet function and inflammatory markers are assessed at baseline, after 7 days of clopidogrel, and after clopidogrel plus aspirin. Genotyping is performed by genome-wide marker and candidate gene analyses, and the relation between loci and phenotype is determined through linkage and family based association testing. Results will be validated against candidate gene results obtained in Caucasians and African Americans. Role: Co-Investigator R01 HL097698 (PI: L. Becker) 3/5/07-2/28/2010 NIH/NHLBI Title: Genome-Wide Association of Platelet Phenotypes The overall goal of this proposal is to identify genes that modify the function of platelets, both under “normal native” conditions, and following low dose ASA. We propose to perform high density single nucleotide polymorphism (SNP) genotyping (550,000 SNPs, using the Illumina HumanHap550 BeadChip) covering the entire genome at an average 6kb density, on the DNA samples from the GeneSTAR participants phenotyped for platelet function. We propose to determine whether any genomic loci are associated with quantitative platelet phenotypes prioritized for high heritability, biological interest, and/or linkage to STR markers, using family based association analysis, with joint modeling of linkage and association. Role: Co-Investigator U01 HL72518-01 (PI: L Becker) 10/01/02-12/31/09 NIH/NHLBI Title: Genotypic Determinants of Aspirin Response in High Risk Families This study characterizes the inhibitory effect of aspirin (ASA) on agonist-induced platelet aggregation and aggregation under shear conditions (PFA-100) in 3000 subjects, half African American and half white. Platelet function and plasma inflammatory markers were measured at baseline and after 14 days of ASA, 81 mg/day, to characterize ASA-response phenotypes. Genotyping analyses will be performed to determine whether ASA responsiveness is heritable and whether it is associated with specific variations in candidate genes. In a 2year continuation of this study, we will also perform linkage analysis of STR markers to identify genomic loci that are linked to important platelet phenotypes, followed by fine mapping using additional STR markers to achieve a density of 1cM. We will also perform analyses for family based associations, haplotypes, and conditional logic regressions to discover whether gene-gene and/or gene-environment interactions may affect important pre- and post-aspirin platelet phenotypes. Role: Co-Investigator AHA #0160347U 7/01-6/03 American Heart Association Title: Platelet polymorphisms and cardiovascular outcome in vascular surgical patients Role: Principal Investigator 1 K08 HL03454-01A1 9/96-8/01 NIH/NHLBI, Clinician Scientist Investigator Award Title: Examination of gender differences in GPIIb-IIIa function Role: Principal Investigator PHS 398/2590 (Rev. 06/09) Page Continuation Format Page