Atherosclerosis susceptibility is a function of both environmental, principally dietary, influences and genetic constitution. Although perhaps 5-10% of the population are genetically resistant and another 5-10% susceptible to atherosclerosis, in the vast majority of the population, disease is a function of environment-gene interactions. In this research proposal, we intend to utilize our expertise in biochemistry and molecular biology and the resouces of the Rockefeller University Hospital Clinical Research Center to define and ultimately to understand the range of human variation in response to diet. Four projects are proposed: 1. Apolipoprotein Gene RFLPs, Lipoprotein Abnormalities and Atherosclerosis Susceptibility. To perform association and linkage studies to infer a role for the apolipoprotein gene loci in lipoprotein abnormalities and myocardial infarction susceptibility. Putative abnormal alleles will be cloned and studied functionally and structrally for causative mutations. 2. Dietary and Genetic Determinants of LDL Cholesterol Levels. To define the range of interindividual responsiveness of LDL cholesterol levels to dietary cholesterol and saturated fat in normal volunteers and patients. To explore the basis for dietary responsiveness with physiological, biochemical and genetic studies. 3. Regulation of Postprandial Lipoprotein Metabolism. To better understand the regulation of chylomicron and chylomicron remnant clearance by studying patients and normal volunteers using the vitamin A-fat tolerance test. The effects of diet and exercise will be studied in normal volunteers as well as drug effects in patients. To define whether delayed chylomicron clearance is due to defects in the particle or in lipoprotein lipase. 4. Dietary and Genetic Determinants of HDL Cholesterol Levels. To recruit individuals with primary increases or decreases in HDL cholesterol levels and determine, by in vivo turnover studies, if the abnormality is in synthesis or catabolism. To study the effects of dietary fat on HDL levels and turnover parameters. To determine the genetic basis underlying individual differences. These studies should provide insights into understanding gene-diet interactions underlying atherosclerosis susceptibility. They will also significantly contribute to the emerging new field of nutritional genetics.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL032435-06
Application #
3343772
Study Section
Nutrition Study Section (NTN)
Project Start
1984-06-01
Project End
1993-05-31
Budget Start
1989-06-01
Budget End
1990-05-31
Support Year
6
Fiscal Year
1989
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Type
Graduate Schools
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Sehayek, Ephraim; Fung, Yee Yan; Yu, Hannah J et al. (2006) A complex plasma plant sterol locus on mouse chromosome 14 has at least two genes regulating intestinal sterol absorption. J Lipid Res 47:2291-6
Vitarius, James A; Sehayek, Ephraim; Breslow, Jan L (2006) Identification of quantitative trait loci affecting body composition in a mouse intercross. Proc Natl Acad Sci U S A 103:19860-5
Soccio, Raymond E; Adams, Rachel M; Maxwell, Kara N et al. (2005) Differential gene regulation of StarD4 and StarD5 cholesterol transfer proteins. Activation of StarD4 by sterol regulatory element-binding protein-2 and StarD5 by endoplasmic reticulum stress. J Biol Chem 280:19410-8
Maxwell, Kara N; Breslow, Jan L (2005) Proprotein convertase subtilisin kexin 9: the third locus implicated in autosomal dominant hypercholesterolemia. Curr Opin Lipidol 16:167-72
Tiemann, Michaela; Han, Zhihua; Soccio, Raymond et al. (2004) Cholesterol feeding of mice expressing cholesterol 7alpha-hydroxylase increases bile acid pool size despite decreased enzyme activity. Proc Natl Acad Sci U S A 101:1846-51
Maxwell, Kara N; Breslow, Jan L (2004) Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc Natl Acad Sci U S A 101:7100-5
Maxwell, Kara N; Soccio, Raymond E; Duncan, Elizabeth M et al. (2003) Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice. J Lipid Res 44:2109-19
Soccio, Raymond E; Breslow, Jan L (2003) StAR-related lipid transfer (START) proteins: mediators of intracellular lipid metabolism. J Biol Chem 278:22183-6
Sehayek, Ephraim; Wang, Rong; Ono, Jennie G et al. (2003) Localization of the PE methylation pathway and SR-BI to the canalicular membrane: evidence for apical PC biosynthesis that may promote biliary excretion of phospholipid and cholesterol. J Lipid Res 44:1605-13
Soccio, Raymond E; Adams, Rachel M; Romanowski, Michael J et al. (2002) The cholesterol-regulated StarD4 gene encodes a StAR-related lipid transfer protein with two closely related homologues, StarD5 and StarD6. Proc Natl Acad Sci U S A 99:6943-8

Showing the most recent 10 out of 69 publications