The central theme of this competitive renewal application for our PPG is based upon three hypotheses: (1) Apolipoprotein (apo) A-l-containing lipoproteins play a major role in atherogenesis;(2) apoB-containing lipoproteins play a major role in atherogenesis;and (3) the properties of the different apolipoprotein domains involved in the regulation of the functions of the apoA-l- and apoB-containing lipoproteins are determined to a major extent by the properties of the amphipathic motifs ubiquitous to apolipoproteins. From this we derive our central theme: Amphipathic motifs (the amphipathic a helix and the amphipathic (3 strand/sheet) are fundamental to a full understanding of the cause and reversal of atherosclerosis. Amphipathic motifs represent the fundamental paradigm guiding all proposed projects. The objectives in the next five years are to continue development of a comprehensive theory of the interaction of amphipathic motifs with lipid and to use this knowledge to: (a) determine the minimal structural features of apoA-l and HDL that are involved in both the assembly of apoA-l -containing lipoproteins and the structure, function and properties of HDL (b) determine the minimal structural features of apoB that are involved in both the biogenesis of apoB-containing lipoproteins and the structure, function and properties of LDL, and (c) apply this knowledge to understand mechanisms involved in prevention and reversal of atherosclerosis and potentially for the development of pharmacological agents. To accomplish these objectives, four projects are proposed: 1) Computational and experimental studies of structure/dynamics of HDL assemblies (Dr. Jere P. Segrest, Project Leader). 2) Molecular mechanisms of biogenesis of apolipoprotein B-containing lipoproteins (Dr. Nassrin Dashti, Project Leader). 3) Peptide modulators of HDL structure-function (Dr. G. M. Anantharamaiah, Project Leader). 4) Biology of apolipoprotein functional mimetics (Dr. David W. Garber, Project Leader). To support these projects, three core facilities are proposed: Core A: Administration and computation (Dr. Segrest), Core B: Peptide synthesis (Dr. Anantharamaiah), and Core C: Cell biology (Dr. Dashti). The proposed studies will contribute to the prevention and reversal of coronary heart disease through information leading to the development of better pharmaceutical agents.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL034343-25
Application #
8242752
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Liu, Lijuan
Project Start
1994-07-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
25
Fiscal Year
2012
Total Cost
$1,437,524
Indirect Cost
$446,128
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
White, C Roger; Giordano, Samantha; Anantharamaiah, G M (2016) High-density lipoprotein, mitochondrial dysfunction and cell survival mechanisms. Chem Phys Lipids 199:161-9
Segrest, Jere P; Jones, Martin K; Catte, Andrea et al. (2015) A robust all-atom model for LCAT generated by homology modeling. J Lipid Res 56:620-34
Datta, Geeta; Kramer, Philip A; Johnson, Michelle S et al. (2015) Bioenergetic programming of macrophages by the apolipoprotein A-I mimetic peptide 4F. Biochem J 467:517-27
White, C Roger; Goldberg, Dennis I; Anantharamaiah, G M (2015) Recent developments in modulating atherogenic lipoproteins. Curr Opin Lipidol 26:369-75
Guo, Lilu; Chen, Zhongyi; Amarnath, Venkataraman et al. (2015) Isolevuglandin-type lipid aldehydes induce the inflammatory response of macrophages by modifying phosphatidylethanolamines and activating the receptor for advanced glycation endproducts. Antioxid Redox Signal 22:1633-45
Namiri-Kalantari, Ryan; Gao, Feng; Chattopadhyay, Arnab et al. (2015) The dual nature of HDL: Anti-Inflammatory and pro-Inflammatory. Biofactors 41:153-9
Navab, Mohamad; Chattopadhyay, Arnab; Hough, Greg et al. (2015) Source and role of intestinally derived lysophosphatidic acid in dyslipidemia and atherosclerosis. J Lipid Res 56:871-87
Segrest, Jere P; Jones, Martin K; Catte, Andrea et al. (2015) Surface Density-Induced Pleating of a Lipid Monolayer Drives Nascent High-Density Lipoprotein Assembly. Structure 23:1214-26
Reddy, Srinivasa T; Navab, Mohamad; Anantharamaiah, Gattadahalli M et al. (2014) Apolipoprotein A-I mimetics. Curr Opin Lipidol 25:304-8
White, C Roger; Garber, David W; Anantharamaiah, G M (2014) Anti-inflammatory and cholesterol-reducing properties of apolipoprotein mimetics: a review. J Lipid Res 55:2007-21

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