Daniel Ory, MD
Alan A and Edith L Wolff Distinguished Professor of Medicine
Molecular basis of Niemann-Pick C disease and the regulation of NPC1 and NPC2 genes in cholesterol homeostasis Read More
|Lab Phone:||(314) 362-8794|
|Lab Location:||BJC Institute of Health 10402|
|Keywords:||Niemann-Pick C, neurodegeneration, NPC1, cholesterol, oxysterols, NPC1 KO/KI models, CNS therapeutics, protein misfolding, high throughput small molecule screens|
Molecular basis of Niemann-Pick C disease and the regulation of NPC1 and NPC2 genes in cholesterol homeostasis
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.
Updated January 2014
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