Daniel S Ory MD
Atherosclerotic coronary artery disease is a major diabetes complication. Work in my laboratory focuses on identification and characterization of genes that function in the uptake, intracellular transport, and export of lipoprotein-derived cholesterol, and on gene programs that regulate cellular cholesterol balance. The goal of our research is to shed light on the molecular mechanisms involved in atherosclerotic lesion formation, and to identify biomarkers for early detection of vascular disease in diabetes.
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 fourbroad areas. First, we study molecular mechanisms of regulation of cholesterol homeostasis. Using an unbiased genetic screen to identify the molecular machinery responsible for cholesterol regulation, we discovered small RNAs (small nucleolar RNAs) that represent a previously unrecognized mode of regulation for cellular cholesterol homeostasis. We are using RNA affinity purification methods to identify the targets of these snoRNAs, and their physiological role is being investigated in conditional knockout and transgenic mouse models. Second, we are using multidisciplinary approaches – photoactivatable cholesterol probes and proteomics – to identify the cholesterol transfer and binding protein responsible for exit of cholesterol from lysosomes. Third, we are developing therapeutics for Niemann-Pick C disease. Current projects are focused on use of “proteostasis regulators” to correct the protein folding defect in the mutant NPC1 protein in our mouse models. Our work in this area has led to two Phase 1 clinical trials and has launched a multicenter Phase 2/3 trial. Fourth, using mass spectrometry-based metabolomics, we have identified candidate cholesterol and lipid-derived metabolites that are being validated in clinical studies as biomarkers in human disorders associated with oxidative stress, including diabetes and Niemann-Pick C disease. These biomarkers are being developed as diagnostic and newborn screening tools.