Daniel S. Ory, M.D.

Internal Medicine
Cell Biology & Physiology
Diabetic Cardiovascular Disease Center

Molecular Cell Biology Program
Biochemistry, Biophysics, and Structural Biology 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:

Castellano BM, Thelen AM, Moldavski O, Feltes M, van der Welle REN, Mydock-McGrane L, Jiang X, van EijKeren RJ, Davies OB, Louie SM, Perera RM, Covey D, Nomura DK, Ory DS, and Zoncu R. Lysosomal cholesterol activates mTORC1 via an SLC38A9-Niemann-Pick C1 signaling complex. Science 2017, 355:1306-1311.

Wei X, Song H, Yin L, Rizzo M, Yang L, Sidhu R, Miller MJ, Ory DS, Semenkovich CF. Endogenous lipid synthesis orchestrates membrane microdomain assembly to promote diet-induced diabetes. Nature 2016, 539:294-298.

Jiang X, Sidu R, Mydock L, Hsu F-F, Covey DF, Scherrer DE, Earley B, Gale SE, Farhat N, Porter FD, Dietzen DJ, Orsini JJ, Berry-Kravis E, Zhang X, Reunert J, Thorsten Marquardt J, Runz H, Giugliani R, Schaffer JE, and Ory DS. Development of a Bile Acid-Based Newborn Screen for Niemann-Pick C Disease. Sci Trans Med 2016 May 4;8(337):337ra63.

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

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.

Last Updated: 7/3/2017 10:18:40 AM

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