Genetic regulation of lipid and lipoprotein metabolism and molecular relationship to atherosclerosis.
Description of Research
The Rader laboratory
is interested in genetic and inflammatory factors that regulate the metabolism and function of plasma lipoproteins and their interaction with the vessel wall in promoting and inhibiting atherogenesis. A variety of basic cell and molecular laboratory techniques, mouse models, and clinical research approaches are used in addressing these questions.
Major ongoing projects include:
1) Inflammatory and genetic factors that regulate the in vivo metabolism of HDL and other lipoproteins. A major current focus is that extracellular lipases are important physiologic and pathophysiologic regulators of lipoprotein metabolism and function and that their expression is both genetically determined and influenced by inflammatory factors. We have cloned several new members of the lipoprotein lipase gene family and are investigating their function and regulation.
2) Molecular and cellular mechanisms by which HDL-associated proteins inhibit atherogenesis and induce regression of atherosclerotic lesions. Somatic gene transfer of HDL-associated proteins is used in mouse models of atherosclerosis in order to study their effects on atherogenesis in vivo. Tissue culture models have been developed in order to reconstruct cellular aspects of the atherosclerotic process in vitro and determine anti-inflammatory effects of HDL proteins.
3) Dietary and genetic regulation of hepatic lipoprotein production. Gene transfer, transgenic, and cell culture approaches are used to study the interaction between specific genes, such as the microsomal transfer protein and diacylglycerol acyltransferase, and dietary manipulation in the regulation of hepatic apoB production in mice. Lipoprotein kinetic studies are also performed in humans using endogenous labeling of apolipoproteins with stable isotopically labeled leucine.
4) Genetic factors associated with premature atherosclerotic disease and high or low levels of HDL cholesterol. Subjects with family history of premature coronary disease or with extremes of HDL cholesterol are recruited and phenotyped for cardiovascular risk factors and clinical and subclinical atherosclerosis. Candidate genes are investigated for their association with subclinical atherosclerosis or variation in HDL cholesterol levels and linkage analysis of sib pairs and large pedigrees will be performed. The overall focus of our research effort is basic cell and molecular laboratory science with translation into animal experiments and ultimately into patient-oriented research in the areas of lipoprotein metabolism and premature atherosclerosis.
6th floor, Biomedical Research Building (BRB) II/III
4th floor Andrew Mutch Building, Presbyterian Medical Center
Degoma EM, Rader DJ: Novel HDL-directed pharmacotherapeutic strategies. Nature reviews. Cardiology 8(5): 266-277, May 2011.
Potteaux S, Gautier EL, Hutchison SB, van Rooijen N, Rader DJ, Thomas MJ, Sorci-Thomas MG, Randolph GJ: Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe-/- mice during disease regression. The Journal of clinical investigation 121(5): 2025-2036, May 2011.
Bauer RC, Stylianou IM, Rader DJ: Functional validation of new pathways in lipoprotein metabolism identified by human genetics. Current opinion in lipidology 22(2): 123-8, Apr 2011.
Mehta NN, Li M, William D, Khera AV, Derohannessian S, Qu L, Ferguson JF, McLaughlin C, Shaikh LH, Shah R, Patel PN, Bradfield JP, He J, Stylianou IM, Hakonarson H, Rader DJ, Reilly MP: The novel atherosclerosis locus at 10q11 regulates plasma CXCL12 levels. European Heart journal 32(8): 963-971, Apr 2011.
Rak K, Rader DJ: Cardiovascular disease: the diet-microbe morbid union. Nature 472(7341): 40-41, Apr 2011.
Toh S-A, Millar JS, Billheimer J, Fuki I, Naik SU, Macphee C, Walker M, Rader DJ: PPARγ activation redirects macrophage cholesterol from fecal excretion to adipose tissue uptake in mice via SR-BI. Biochemical pharmacology 81(7): 934-941, Apr 2011.
Nijstad N, de Boer JF, Lagor WR, Toelle M, Usher D, Annema W, der Giet M van, Rader DJ, Tietge UJF: Overexpression of apolipoprotein O does not impact on plasma HDL levels or functionality in human apolipoprotein A-I transgenic mice. Biochimica et biophysica acta 1811(4): 294-9, Apr 2011.
Edmondson AC, Braund PS, Stylianou IM, Khera AV, Nelson CP, Wolfe ML, Derohannessian SL, Keating BJ, Qu L, He J, Tobin MD, Tomaszewski M, Baumert J, Klopp N, Döring A, Thorand B, Li M, Reilly MP, Koenig W, Samani NJ, Rader DJ: Dense Genotyping of Candidate Gene Loci Identifies Variants Associated With High-Density Lipoprotein Cholesterol. Circulation 4(2): 145-155, Apr 2011.
Magge SN, Stettler N, Koren D, Levitt Katz LE, Gallagher PR, Mohler ER 3rd, Rader DJ.: Adiponectin Is Associated with Favorable Lipoprotein Profile, Independent of BMI and Insulin Resistance, in Adolescents. J Clin Endocrinol Metab
96(5): 1549-1554, May 2011.
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Last updated: 03/07/2014
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