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
Joshi AA, Lerman JB, Aberra TM, Afshar M, Teague HL, Rodante JA, Krishnamoorthy P, Ng Q, Aridi TZ, Salahuddin T, Natarajan B, Lockshin BN, Ahlman MA, Chen MY, Rader DJ, Reilly M, Remaley AT, Bluemke DA, Playford MP, Gelfand JM, Mehta NN: GlycA Is a Novel Biomarker of Inflammation and Subclinical Cardiovascular Disease in Psoriasis. Circ Res : 2016.
Jacoby DS, Rader DJ: Improving cardiovascular outcomes by intensifying low density lipoprotein lowering therapy in high-risk patients. Eur Heart J : 2016.
van Capelleveen JC, Kastelein JJ, Zwinderman AH, van Deventer SJ, Collins HL, Adelman SJ, Round P, Ford J, Rader DJ, Hovingh GK.: Effects of the cholesteryl ester transfer protein inhibitor, TA-8995, on cholesterol efflux capacity and high-density lipoprotein particle subclasses. J Clin Lipidol 10 (5): 1137-1144.e3,2016.
Beheshtian A, Shitole SG, Segal AZ, Leifer D, Tracy RP, Rader DJ, Devereux RB, Kizer JR: Lipoprotein (a) level, apolipoprotein (a) size, and risk of unexplained ischemic stroke in young and middle-aged adults. Atherosclerosis 253 : 47-53,2016.
Quach D, Vitali C, La FM, Xiao AX, Millar JS, Tang C, Rader DJ, Phillips MC, Lyssenko NN: Cell lipid metabolism modulators 2-bromopalmitate, D609, monensin, U18666A and probucol shift discoidal HDL formation to the smaller-sized particles: implications for the mechanism of HDL assembly. Biochim Biophys Acta 1861 : 1968-1979,2016.
Saleheen D, Rader DJ, Voight BF: Disentangling the Causal Association of Plasma Lipid Traits and Type 2 Diabetes Using Human Genetics. JAMA Cardiol 1 (6): 631-633,2016.
Roth EM, Moriarty PM, Bergeron J, Langslet G, Manvelian G, Zhao J, Baccara-Dinet MT, Rader DJ; ODYSSEY CHOICE I investigators: A phase III randomized trial evaluating alirocumab 300 mg every 4 weeks as monotherapy or add-on to statin: ODYSSEY CHOICE I. Atherosclerosis 254 : 254-262,2016.
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