Research Abstract:
Cellular cholesterol requirements are met through de novo cholesterol synthesis and uptake of lipoprotein cholesterol. These homeostatic responses are tightly regulated at multiple cholesterol transfer steps and through a negative feedback loop that responds to elevations of membrane cholesterol in the endoplasmic reticulum (ER). Alterations in sterol sensing and trafficking pathways contribute to human inborn errors of metabolism (e.g., Niemann-Pick C disease) and to acquired disease states (e.g., atherosclerosis). The goals of our laboratory are elucidate mechanisms governing these critical cholesterol homeostatic pathways, and to translate our findings to develop biomarkers for prevention and treatment of human disease.
Our work is focused in three broad areas. First, we study molecular mechanisms of regulation of cholesterol homeostasis. In a multidisciplinary approach, we are using biophysical, cell biology and steroid chemistry methods to understand the mechanism through which oxygenated forms of cholesterol (“oxysterols”) exert their homeostatic effects. These studies are complemented by an unbiased genetic screen that seeks to identify the molecular machinery responsible for regulation of cellular cholesterol balance. These studies have led to discovery of small RNAs that represent a previously unrecognized mode of regulation for cellular cholesterol homeostasis. The function of candidate molecules identified by this approach are being examined in mouse models of atherosclerosis. Second, we are investigating the function and regulation of the Niemann-Pick C1 (NPC1) protein in cell-based and animal models. These studies involve use of high throughput screens to identify small molecule “chaperones” that correct the protein-folding defect responsible for NPC1 disease. Candidate compounds are being investigated in vivo in a mouse model of NPC1 disease. Third, using mass spectrometry-based lipidomic, we have identified candidate lipid metabolites that are being validated in clinical studies as biomarkers in human disorders associated with oxidative stress, including diabetes and Niemann-Pick C disease.
Selected Publications:
Lange Y, Steck TL, Ye J, Lanier MH, Molugu V, and Ory DS. Regulation of a 27-hydrocholesterol-dependent sterol homeostatic pathway by active plasma membrane cholesterol. J Lipid Res 2009 50:1881-1888.
Gale SE, Westover EJ, Merlin S, Scherrer DE, Han X, Xiuhong Z, Brockman HL, Brown RE, Covey DF, Schaffer JE, Schlesinger P, and Ory DS. Side-chain oxygenated cholesterol regulates cellular cholesterol homeostasis through direct sterol-membrane interactions. J Biol Chem. 2009 284:1755-1764.
Zhang J, Coleman T, Langmade SJ, Scherrer DE, Lane L, Lanier MH, Feng C, Sands M, Schaffer JE, Semenkovich C and Ory DS. Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking. J Clin Invest 2008 118: 2281-2290.
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 2008 283:8229-8236.
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.
Last Updated: 09/17/2009 |