My laboratory studies the pathophysiology of hemorrhage and thrombosis, focusing on the mechanisms that promote and inhibit platelet adhesion. Von Willebrand factor (VWF) is a multimeric protein that mediates platelet adhesion to sites of vascular injury and stabilizes blood coagulation factor VIII; these interactions are essential for hemostasis. Von Willebrand disease (VWD) is caused by deficiency of VWF, and is the most common inherited bleeding disorder. Specific domains of VWF interact with platelet receptor proteins, and binding is regulated allosterically. A single VWF multimer can be enormous, up to 100 micrometers in length, and the largest multimers are the most hemostatically active. We are investigating the mechanism of VWF multimer assembly and the regulation of VWF binding to its receptors on platelets. VWF assembly into large multimers is required to prevent bleeding and, conversely, the proteolytic cleavage of VWF multimers is required to prevent thrombosis. We recently cloned a metalloprotease with a complex multidomain structure, ADAMTS13, which participates in the feedback inhibition of VWF function by cleaving a Tyr-Met bond in the center of the VWF subunit. Interestingly, VWF cleavage by ADAMTS13 is regulated by tensile stress, so that VWF only becomes susceptible when it is stretched at the site of a growing platelet thrombus. We are determining how various domains of ADAMTS13 cooperate to recognize and cleave VWF. Congenital or acquired deficiency of ADAMTS13 causes life-threatening microvascular thrombosis (thrombotic thrombocytopenic purpura), and we are investigating the clinical utility of ADAMTS13 assays in the diagnosis and treatment of thrombotic thrombocyotpenic purpura.
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Model for the assembly, tubular packing, and secretion of VWF multimers
(A and B) In the ER, proVWF subunits dimerize through disulfide bonds between C-terminal CK domains (small gray spheres). The propeptide consists of domains D1 ("1," yellow) and D2 ("2," orange) and is linked to D'D3 of the mature subunit ("3," blue) by a furin cleavage site (green). Two potential orientations of the propeptide are distinguished by whether homodimer contacts involve domain D1 (A) or D2 (B). In either case, pH-dependent interactions bring two D′D3 domains together and facilitate intersubunit disulfide bond formation.
From: Huang RH, Wang Y, Roth R, Yu X, Purvis AR, Heuser JE, Egelman EH, Sadler JE
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| 1969-1973 | A.B. in Chemistry (summa cum laude), Princeton University, Princeton, NJ |
| 1973-1979 | Duke University Medical Center, Durham, NC
1978 - Ph.D. in Biochemistry, Robert L. Hill, advisor 1979 - M.D. |
| 1979-1981 | Duke University Medical Center, Durham, NC
1979 - Research Associate, Department of Biochemistry 1979-1980 - Intern in Medicine 1980-1981 - Junior Assistant Resident in Medicine |
| 1981-1984 | University of Washington, Seattle, WA
1981-1984 - Fellow in Hematology, Department of Medicine 1982-1984 - Associate, Department of Pharmacology 1982-1984 - Associate, Howard Hughes Medical Institute at Seattle |
| 1984-1996 | Associate Investigator, Howard Hughes Medical Institute at St. Louis |
| 1984-1989 | Assistant Professor of Medicine, Washington University School of Medicine, St. Louis, MO |
| 1989-1993 | Associate Professor of Medicine, Washington University School of Medicine, St. Louis, MO |
| 1985-1993 | Assistant Professor of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO |
| 1993-present | Professor of Medicine, Hematology Division, Washington University School of Medicine, St. Louis, MO |
| 1993-present | Professor of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO |
| 1996-2008 | Investigator, Howard Hughes Medical Institute at St. Louis |
| 2009-present | Chief, Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO |
| 1990-1991 | Molecular Biology Steering Committee, Division of Biology and Biomedical Sciences |
| 1989-1991 | Metabolic Regulation Preliminary Examination Committee, Division of Biology and Biomedical Sciences
1991 - Chairman |
| 1989-1993 | MA/MD Program Committee, Division of Biology and Biomedical Sciences |
| 1991 | Ad Hoc Committee to Examine the Biomedical Research Computing Facility Services |
| 1992-1999 | Molecular Cell Biology Steering Committee, Division of Biology and Biomedical Sciences |
| 1992-1995 | Transfusion Review Committee, The Jewish Hospital of St. Louis |
| 1996-present | Transfusion Review Committee, Barnes-Jewish Hospital |
| 2003-2006 | Academic Freedom and Tenure Hearing Committee |
| 2007-2010 | Co-director, Hematology-Oncology Fellowship Program |
| 1982 | Diplomate, American Board of Internal Medicine |
| 1973 | Everett S. Wallis Prize in Organic Chemistry, Princeton University |
| 1973 | Robert Thornton McCay Prize (Physical Chemistry), Princeton University |
| 1973 | Phi Beta Kappa |
| 1976 | Alpha Omega Alpha |
| 1988 | American Society for Clinical Investigation |
| 1993 | Association of American Physicians |
| 1995 | Investigator Recognition Award, Seventh Biennial Awards for Contributions to Hemostasis, ISTH, Jerusalem, Israel |
| 1997 | Investigator Recognition Award, Eighth Biennial Awards for Contributions to Hemostasis, ISTH, Florence, Italy |
| 1998 | William Dameshek Prize, American Society of Hematology |
| 1998 | Fellow, American Association for the Advancement of Science, Medical Sciences (N) |
| 2001 | Distinguished Career Award, Tenth Biennial Awards for Contributions to Hemostasis, ISTH, Paris, France |
| 2001 | Fellow, American Heart Association |
| 1988-1992 | Editorial Board, Blood |
| 1989-1993 | Editorial Board, The Journal of Biological Chemistry |
| 1993-2002 | Associate Editor, Blood |
| 1993-present | Editorial Advisory Board, Biochemistry |
| 1998-2010 | Board of Consulting Editors, Journal of Clinical Investigation |
| 1999-2002 | Advisory Board, Thrombosis and Haemostasis |
| 2003-2006 | Advisory Board, Journal of Thrombosis and Haemostasis |
| 2003-2007 | Editorial Advisory Board, ASBMB Today |
| 2005-2007 | Faculty of 1000 Medicine Project |
| 2006-2007 | Editorial Board, Arteriosclerosis Thrombosis and Vascular Biology |
| 2007-2013 | Editorial Board, Journal of Thrombosis and Haemostasis |
| 2008-present | Editorial Board, Blood |
| 2012-present | Board of Consulting Editors, Journal of Clinical Investigation |
| 1978-present | Sigma Xi |
| 1981-present | American Association for the Advancement of Science |
| 1985-present | American Society for Biochemistry and Molecular Biology |
| 1985-present | American Society of Hematology
1989-1992 - Scientific Subcommittee on Hemostasis 1994-1996 - Scientific Subcommittee on Hemostasis 1994 - Program Committee 1995 - Co-Chair, Scientific Program Committee 1996 - Program Committee 1997 - Chair, Scientific Program Committee 1998-2002 - Councillor, Executive Committee 2003-2006 - Treasurer 2004-2006 - Ad Hoc Minority Committee 2008 - Co-Chair, Committee on Investment and Audit 2008 - Co-Chair, Scientific Program Committee 2009 - Vice President 2010 - President-Elect 2011 - President |
| 1986-present | The Protein Society |
| 1987-present | American Federation for Medical Research |
| 1987-present | International Society on Thrombosis and Haemostasis
1988-2006 - Subcommittee on von Willebrand Factor, Scientific and Standardization Committee 1988-1989 - Co-Chairman 1992-1994 - Co-Chairman 1994-1997 - Chairman 2003-2006 - Chair, Working Party on von Willebrand Disease Classification 1992-1998 - Scientific and Standardization Committee Class of 1998 1996-1997 - Member-at-large, Executive Committee, Scientific and Standardization Committee 1996-2002 - Executive Council Class of 2002 1998-present - Senior Advisory Council, Scientific and Standardization Committee 1998-2003 - Chairman, Standing Committee on Publications 2007 - Scientific Program Committee, XXI ISTH Congress, Geneva 2009 - International Scientific Advisory Board, XXII ISTH Congress, Boston 2011 - Scientific Program Committee, XXIII ISTH Congress, Kyoto |
| 1987-present | American Heart Association
1987-1997 - Member, Council on Thrombosis 1997-present - Fellow, Council on Arteriosclerosis, Thrombosis, and Vascular Biology 1988-1990 - Executive Committee, Council on Thrombosis 1998-2000 - Executive Committee, Council on Arteriosclerosis, Thrombosis, and Vascular Biology 1998-1999 - Vice Chairman, Program Committee (Thrombosis Section), Council on Arteriosclerosis, Thrombosis, and Vascular Biology 1999-2000 - Chairman, Program Committee (Thrombosis Section), Council on Arteriosclerosis, Thrombosis, and Vascular Biology |
| 1988-present | American Society for Clinical Investigation |
| 1993-present | Association of American Physicians |
| 1993-1997 | NIH Hematology Study Section 1
1995-1997 - Chairman |
| 1995-present | Molecular Medicine Society |
| 1996 | Vice-Chair, Gordon Conference on Hemostasis |
| 1998 | Chair, Gordon Conference on Hemostasis |
| 2004-2008 | NIH NHLBI von Willebrand Disease Working Group |
| 2006-2008 | NCRR Protocol Review Committee for the Rare Diseases Clinical Research Network |
| 2006 | NIH NHLBI Strategic Planning Level 1 Working Group on Diagnosis and Treatment of Thrombotic Disorders |
| 2009 | NIH NHLBI State of the Science Symposium in Transfusion Medicine and Hemostasis/Thrombosis, September 14-15, 2009, Thrombosis/Hemostasis External Panel |