Daniel S. Ory, M.D.

Professor
Internal Medicine
Cardiology
Cell Biology & Physiology
Diabetic Cardiovascular Disease Center

Molecular Cell Biology Program
Biochemistry Program

  • 314-362-8737

  • 362-8732

  • 314-747-0264

  • 8086

  • 10618 BJCIH

  • dory@wustl.edu

  • http://dcdc.wustl.edu/

  • cholesterol, cholesterol trafficking, non-coding RNA, steroidogenesis, lysosomal disease, Niemann-Pick C, neurodegeneration, oxysterols, metabolomics, newborn screening

  • Study of regulation of cholesterol homeostasis, and role of cholesterol in neurodegeneration and steroidogenesis

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 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.

Selected Publications:

Jinn S, Brandis KA, Ren, A, Chacko A, Dudley-Rucker N, Fujiwara H, Jiang H, Olsen BN, Schaffer JE, and Ory DS. snoRNA U17 regulates cellular cholesterol trafficking, Cell Metabolism, 2015, 21:855-867.

Praggastis M, Tortelli B, Zhang J, Fujiwara H, Sidhu R, Chacko A, Chen Z, Lieberman AP, Davidson C, Walkley SU, Pipalia NH, Maxfield FR, Schaffer JE, and Ory DS. A murine Niemann-Pick C1 (NPC1) I1061T knockin model recapitulates the pathological features of the most prevalent human disease allele, J Neuroscience 2015, 35:8091-8106.

Bielska A, Olsen B, Gale SE, Mydock L, Krishnan K, Baker N, Schlesinger P, Covey D, Ory DS. Side-chain oxysterols modulate cholesterol accessibility through membrane remodeling. Biochemistry 2014, 53: 3042-3051

Tortelli B, Fujiwara H, Bagel JH, Zhang J, Sidhu R, Jiang X, Yanjanin NM, Kanakatti Shankar R, Carillo-Carasco N, Heiss J, Ottinger E, Porter FD, Schaffer JE, Vite CH, Ory DS. Cholesterol homeostatic responses provide biomarkers for monitoring treatment of the neurodegenerative disease Niemann-Pick C1 (NPC1). Hum Mol Genet 2014, 23:6022-6033.

Brandis KA, Jinn S, Langmade SJ, Dudley-Rucker N, Jiang H, Ren A, Goldberg A, Schaffer JE, and Ory DS. Box C/D snoRNA U60 Regulates Intracellular Cholesterol Trafficking. J Biol Chem 2013 288:35703-35713.

Olsen BN, Bielska AA, Lee T, Daily MD, Covey DF, Schlesinger PH, Baker NA, and Ory DS. The structural basis of cholesterol accessibility in membranes. Biophys J 2013 105:1838-1847.

Fan M, Sidhu R, Fujiwara H, Tortelli B, Zhang J, Davidson C, Walkley SU, Bagel JH, Vite C, Yanjanin NM, Porter FD, Schaffer JE, and Ory DS. Identification of plasma biomarkers for human Niemann-Pick C1 (NPC1) disease biomarkers through sphingolipid profiling. J Lipid Res 2013, 54(10):2800-14.

Cote M, Misasi J, Ren T, Bruchez A, Lee K, Filone CM, Hensley L, Ory DS, Li Q, Chandran K, and Cunningham J. Small molecule inhibitors reveal that Niemann-Pick C1 is essential for Ebola virus infection. Nature, 2011, 477:344-348.

Michel CI, Holley CL, Scruggs BS, Sidhu R, Brookheart RT, Listenberger LL, Behlke MA, Ory DS and Schaffer JE. Small nucleolar RNAs U32a, U33 and U35a are critical mediators of metabolic stress. Cell Metabolism, 2011, 14:33-44

Porter FD, Scherrer DE, Lanier MS, Langmade SJ, Molugu V, Gale SE, Olzeski D, Sidhu R, Dietzen D, Wassif CA, Yanjanin NM, Marso SP, House J, Vite C, Schaffer JE and Ory DS. Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Science Trans Med 2010, 2:58ra81.

Last Updated: 6/16/2015 4:01:50 PM

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