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
Dunbar RL, Goel H, Tuteja S, Song WL, Nathanson G, Babar Z, Lalic D, Gelfand JM, Rader DJ, Grove GL: Measuring Physical Stigmata of Niacin-Associated Skin Toxicity by Colorimetry, White-Light Spectroscopy, Laser Doppler Flowmetry, and Thermometry in Combination with Symptom Perception Scoring: Methods to Aid Development of Niacin Mimetics. J Lipid Res 58 (4): 783-797,2017.
Cuchel M, Raper AC, Conlon DM, Pryma DA, Freifelder RH, Poria R, Cromley D, Li X, Dunbar RL, French B, Qu L, Farver W, Su CC, Lund-Katz S, Baer A, Ruotolo G, Akerblad P, Ryan CS, Xiao L, Kirchgessner TG, Millar JS, Billheimer JT, Rader DJ: A Novel Approach to Measuring Macrophage-specific Reverse Cholesterol Transport in Vivo in Humans. J Lipid Res 58 (4): 752-762,2017.
Cayo MA, Mallanna SK, Di Furio F, Jing R, Tolliver LB, Bures M, Urick A, Noto FK, Pashos EE, Greseth MD, Czarnecki M, Traktman P, Yang W, Morrisey EE, Grompe M, Rader DJ, Duncan SA: A Drug Screen using Human iPSC-Derived Hepatocyte-like Cells Reveals Cardiac Glycosides as a Potential Treatment for Hypercholesterolemia. Cell Stem Cell 20 (4): 478-489.e%,2017.
Saleheen D, Natarajan P, Armean IM, Zhao W, Rasheed A, Khetarpal SA, Won HH, Karczewski KJ, O'Donnell-Luria AH, Samocha KE, Weisburd B, Gupta N, Zaidi M, Samuel M, Imran A, Abbas S, Majeed F, Ishaq M, Akhtar S, Trindade K, Mucksavage M, Qamar N, Zaman KS, Yaqoob Z, Saghir T, Rizvi SN, Memon A, Hayyat Mallick N, Ishaq M, Rasheed SZ, Memon FU, Mahmood K, Ahmed N, Do R, Krauss RM, MacArthur DG, Gabriel S, Lander ES, Daly MJ, Frossard P, Danesh J, Rader DJ, Kathiresan S.: Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature 544 (7649): 235-239,2017.
Kuwano T, Bi X, Cipollari E, Yasuda T, Lagor WR, Szapary HJ, Tohyama J, Millar JS, Billheimer JT, Lyssenko NN, Rader DJ: Overexpression and deletion of phospholipid transfer protein reduce HDL mass and cholesterol efflux capacity but not macrophage reverse cholesterol transport. J Lipid Res 58 (4): 731-741,2017.
Khera AV, Demler O, Adelman SJ, Collins HL, Glynn RJ, Ridker PM, Rader DJ,
Mora S: Cholesterol Efflux Capacity, HDL Particle Number, and Incident
Cardiovascular Events. An Analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin). Circulation. : 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, Weber C: Vascular CXCR4 Limits Atherosclerosis by Maintaining Arterial Integrity: Evidence from Mouse and Human Studies. Circulation. : 2017.
Stitziel NO, Khera AV, Wang X, Bierhals AJ, Vourakis AC, Sperry AE, Natarajan P, Klarin D, Emdin CA, Zekavat SM, Nomura A, Erdmann J, Schunkert H, Samani NJ, Kraus WE, Shah SH, Yu B, Boerwinkle E, Rader DJ, Gupta N, Frossard PM, Rasheed A, Danesh J, Lander ES, Gabriel S, Saleheen D, Musunuru K, Kathiresan S; PROMIS and Myocardial Infarction Genetics Consortium Investigators: ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. J Am Coll Cardiol 69 (16): 2054-2063,2017.
Bi X, Pashos EE, Cuchel M, Lyssenko NN, Hernandez M, Picataggi A, McParland J, Yang W, Liu Y, Yan R, Yu C, DerOhannessian SL, Phillips MC, Morrisey EE, Duncan SA, Rader DJ: ATP-Binding Cassette Transporter A1 Deficiency in Human Induced Pluripotent Stem Cell-Derived Hepatocytes Abrogates HDL Biogenesis and Enhances Triglyceride Secretion. EBioMedicine. 18 : 139-145,2017.
Pashos EE, Park Y, Wang X, Raghavan A, Yang W, Abbey D, Peters DT, Arbelaez J, Hernandez M, Kuperwasser N, Li W, Lian Z, Liu Y, Lv W, Lytle-Gabbin SL, Marchadier DH, Rogov P, Shi J, Slovik KJ, Stylianou IM, Wang L, Yan R, Zhang X, Kathiresan S, Duncan SA, Mikkelsen TS, Morrisey EE, Rader DJ, Brown CD, Musunuru K: Large, Diverse Population Cohorts of hiPSCs and Derived Hepatocyte-like Cells Reveal Functional Genetic Variation at Blood Lipid-Associated Loci. Cell Stem Cell 20 (4): 558-570,2017.
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