Description of Research Expertise:
The Rader laboratory is focused on two major themes: 1) novel pathways regulating lipid and lipoprotein metabolism and atherosclerosis inspired by unbiased studies of human genetics; 2) factors regulating the structure and function of high density lipoproteins and the process of reverse cholesterol transport and their relationship to atherosclerosis. A variety of basic cell and molecular laboratory techniques, mouse models, and translational research approaches are used in addressing these questions.
Some examples of ongoing projects are:
1) The roles of sortilin (gene SORT1) and tribbles-1 (gene TRIB1) in lipoprotein metabolism and atherosclerosis. Variants at the SORT1 locus are among the most strongly associated with LDL cholesterol and (coronary artery disease) in the human genome, and variants at the TRIB1 locus are significantly associated with all major plasma lipid traits and CAD. A variety of tissue-specific deleted mouse models, gene targeting in iPS cells with differentiation to hepatocytes, and cell biologic and biochemical approaches are being employed.
2) Functional genomics and mechanistic studies of a number of additional genes at loci significantly associated with lipid and metabolic traits, CAD, or other cardiovascular traits. Most of these genes harbor rare coding variants associated with these traits. In addition to elucidating fundamental mechanisms by which the protein influences relevant biology, the influence of specific mutations on protein structure and function are being explored.
3) Molecular regulation of HDLmetabolism and reverse cholesterol transport using cells, mice, and humans
4) Deep phenotyping of humans with low-frequency and rare variants in genes influencing lipid and cardiovascular traits, including the generation of iPS cells and differentiation to a variety of relevant cell types
11th floor, Smilow Center for Translational Research
9th floor Maloney Building, Hospital of The University of Pennsylvania
Dron JS, Wang J, Low-Kam C, Khetarpal SA, Robinson JF, McIntyre AD, Ban MR, Cao H, Rhainds D, Dubé MP, Rader DJ, Lettre G, Tardif JC: Polygenic determinants in extremes of high-density lipoprotein cholesterol. J Lipid Res : 2017.
Zhao W, Rasheed A, Tikkanen E, Lee JJ, Butterworth AS, Howson JMM, Assimes TL, Chowdhury R, Orho-Melander M, Damrauer S, Small A, Asma S, Imamura M, Yamauch T, Chambers JC, Chen P, Sapkota BR, Shah N, Jabeen S, Surendran P, Lu Y, Zhang W, Imran A, Abbas S, Majeed F, Trindade K, Qamar N, Mallick NH, Yaqoob Z, Saghir T, Rizvi SNH, Memon A, Rasheed SZ, Memon FU, Mehmood K, Ahmed N, Qureshi IH, Tanveer-Us-Salam, Iqbal W, Malik U, Mehra N, Kuo JZ, Sheu WH, Guo X, Hsiung CA, Juang JJ, Taylor KD, Hung YJ, Lee WJ: Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease. Nat Genet : 2017.
Tuteja S, Wang L, Dunbar RL, Chen J, DerOhannessian S, Marcovina SM, Elam M, Lader E: Genetic coding variants in the niacin receptor, hydroxyl-carboxylic acid receptor 2, and response to niacin therapy. Pharmacogenet Genomics. 27 (8): 285-293,2017.
Bajaj A, Damrauer SM, Anderson AH, Xie D, Budoff MJ, Go AS, He J, Lash JP, Ojo A, Post WS, Rahman M, Reilly MP, Saleheen D, Townsend RR, Chen J: Lipoprotein(a) and Risk of Myocardial Infarction and Death in Chronic Kidney Disease: Findings From the CRIC Study (Chronic Renal Insufficiency Cohort). Arterioscler Thromb Vasc Biol : 2017.
Koekemoer AL, Codd V, Masca NGD, Nelson CP, Musameh MD, Kaess BM, Hengstenberg C, Rader DJ: Large-Scale Analysis of Determinants, Stability, and Heritability of High-Density Lipoprotein Cholesterol Efflux Capacity. Arterioscler Thromb Vasc Biol : 2017.
Khetarpal SA, Zeng X, Millar JS, Vitali C, Somasundara AVH, Zanoni P, Landro JA, Barucci N, Zavadoski WJ, Sun Z, de Haard H, Toth IV, Peloso GM, Natarajan P, Cuchel M, Lund-Katz S, Phillips MC, Tall AR, Kathiresan S, DaSilva-Jardine P, Yates NA: A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels. Nat Med : 2017.
Small AM, Kiss DH, Zlatsin Y, Birtwell DL, Williams H, Guerraty MA, Han Y, Anwaruddin S, Holmes JH, Chirinos JA, Wilensky RL, Giri J: Text mining applied to electronic cardiovascular procedure reports to identify patients with trileaflet aortic stenosis and coronary artery disease. J Biomed Inform 72 : 77-84,2017.
Dunbar RL, Movva R, Bloedon LT, Duffy D, Norris RB, Navab M, Fogelman AM: Oral Apolipoprotein A-I Mimetic D-4F Lowers HDL-Inflammatory Index in High-Risk Patients: A First-in-Human Multiple-Dose, Randomized Controlled Trial. Clin Transl Sci : 2017.
Döring Y, Noels H, van der Vorst EPC, Neideck C, Egea V, Drechsler M, Mandl M, Pawig LB, Jansen Y, Schröder K, Bidzhekov K, Megens RTA, Theelen W, Klinkhammer BM, Boor P, Schurgers LJ, van Gorp RH, Ries C, Kusters PJH, van der Wal AC, Hackeng TM, Gäbel G, Brandes RP, Soehnlein O, Lutgens E, Vestweber D, Teupser D, Holdt LM, Rader DJ, Saleheen D: Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity: Evidence from Mouse and Human Studies. Circulation. 136 (4): 388-403,2017.
Saleheen D, Haycock PC, Zhao W, Rasheed A, Taleb A, Imran A, Abbas S, Majeed F, Akhtar S, Qamar N, Zaman KS, Yaqoob Z, Saghir T, Rizvi SN, Memon A, Mallick NH, Ishaq M, Rasheed SZ, Memon FU, Mahmood K, Ahmed N, Frossard P, Tsimikas S, Witztum JL, Marcovina S, Sandhu M, Rader DJ: Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a Mendelian randomisation analysis. Lancet Diabetes Endocrinol 5 (7): 524-533,2017.
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