Washington University School of Medicine - Cardiovascular Division - Center for Cardiovascular Research
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Daniel
S. Ory, M.D. Bio Sketch Current Research Recent Publications Experimental Protocol/Reagents Associate Professor of Medicine, Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO Clinical Sciences Research Building, North Tower, Room 827 Harvard
College, Cambridge, Massachusetts, A.B., 1982 1986
- 1989: Intern and Resident, Department of Medicine, Brigham & Women's
Hospital, Harvard Medical School, Boston, MA Honors: 1980 John Harvard Scholarship Cholesterol is an essential component of the plasma membrane in animal cells, regulating membrane fluidity and the formation of lipid microdomains, such as rafts and caveolae. To perform these functions, both the content and cellular distribution of membrane cholesterol must be maintained. Insight into these mechanisms has come from the study of genes that are mutated in the human Niemann-Pick type C (NPC) disease, a progressive neurodegenerative cholesterol storage disorder. The major disease locus encodes for NPC1, a polytopic integral membrane protein that shares sequence homology with the sterol-sensing domains of HMG-CoA reductase and SREBP cleavage-activating protein (SCAP), and localizes to a dynamic late endosomal compartment. Our studies have shown that NPC1 regulates sterol homeostasis through the generation of low-density lipoprotein (LDL) cholesterol-derived oxysterols. The goals of studies in the Ory lab are to understand the basic molecular mechanisms in regulation of cholesterol homeostasis, and the function of the NPC1 protein. First, our studies involve genetic screens in cultured cells to identify molecular machinery involved in intracellular cholesterol trafficking, which will then be studied in mouse models. In an interdisciplinary approach, we are using biophysical, cell biology, steroid chemistry and lipidomic methods to understand the mechanism through which oxysterols exert their homeostatic effects. These studies have led to identification of candidate cholesterol metabolites that are being examined as biomarkers for atherosclerosis and diabetes in human populations. Second, a major effort in the lab is to understand how NPC1 loss of function contributes to disease. The role of NPC1 in cholesterol trafficking in macrophages is being examined in mouse models of atherosclerosis, and the mechanism by which NPC1 loss of function contributes to neuronal cell death is being studied in a mouse knockout model. The latter studies have led to identification of novel approaches to slow the progression of neurodegeneration. Together, these studies may shed light on the pathogenesis of atherosclerotic vascular diseases, such as coronary artery disease, and provide new insight into the role of cholesterol in neurodegeneration. Gelsthorpe M, Baumann N, Millard EE, Gale SE, Langmade SJ, Schaffer JE and Ory DS. NPC1 I1061T mutant encodes a functional protein that is selected for ER-associated degradation due to protein misfolding. J Biol Chem., published 23 January 2008, 10.1074/jbc.M708735200 Langmade SJ, Gale SE, Frolov A, Mohri I, Suzuki K, Mellon SH, Walkley SU, Schaffer JE, and Ory DS. Pregnane X receptor (PXR) activation: A mechanism for neuroprotection in a mouse model of Niemann-Pick C disease. Proc Natl Acad Sci 2006, 103:13807-13812. Gale SE, Frolov A, Han X, Bickel, PE, Cao L, Bowcock A, Schaffer JE, Ory DS. A regulatory role for AGPAT2 in adipocyte differentiation. J Biol Chem 2006, 281:11082-11089. Millard EE, Scherrer D, Langmade, SJ, Zhang J, Gale SE, Dudley, N, Crowley, JR, Schaffer JE, Ory DS. The sterol-sensing domain of the Niemann-Pick C1 (NPC1) protein regulates trafficking of low-density lipoprotein cholesterol. J Biol Chem 2005 280:28581-90. Ory, DS. Nuclear receptor signaling in the control of cholesterol homeostasis: Have the orphans found a home? Circ Res 2004, 95:660-70. Ory, DS. The Niemann-Pick disease genes: regulators of cellular cholesterol homeostasis. Trends Trends Cardiovasc Med. 2004 Feb;14:66-72. Zhang J, Dudley-Rucker N, Crowley JR, Lopez-Perez E, Issandou M, Schaffer JE, and Ory DS.The steroidal analog GW707 activates the SREBP pathway through disruption of intracellular cholesterol trafficking. J Lipid Res. 2004 Feb;45:223-31. Frolov A, Zielinski SE, Crowley JR, Dudley-Rucker N, Schaffer JE, and Ory DS.NPC1 and NPC2 regulate cellular cholesterol homeostasis through generation of LDL cholesterol-derived oxysterols. J Biol Chem 2003. 278: 25517-25.
Center
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