Project 1 of this Program will address the role of altered albumin and the maleyl-albumin receptor as a general mediator of phagocyte recruitment. The hypothesis that in vivo modification of LDL leads to recognition by the scavenger receptor (acetyl-LDL receptor) will also be tested. In Project 2 the cDNA for the human scavenger receptor will be isolated, sequenced and used to quantitate receptor mRNA levels. The mechanisms regulating the intracellular distribution of free cholesterol in human monocyte-macrophages will be studied, and the hypothesis that bacterial lipopoly-saccharide- lipoprotein complexes play a role in atherosclerosis will be tested. Project 3 will isolate and characterize both a chemotactic factor and an inhibitor of monocyte chemotaxis which are produced by endothelial cells. The mechanisms regulating transendothelial macromolecular transport including monocyte adherence and diapedesis will be studied in Projects 3 and 5. Project 4 will utilize a new in vitro system to determine the mechanisms by which lipoproteins are retained in the artery wall, the receptor recognition of these lipoproteins, and the mechanisms of monocyte conversion to foam cells in the subendothelial space. Project 5 will use ultra-rapid freezing without chemical fixation for freeze- fracture studies to determine the details of the association of lipoproteins and/or lipids with the extracellular matrix in the artery wall. The three dimensional structure of the endothelial glycocalyx in its """"""""native"""""""" state and the structural interactions of the glycocalyx with monocytes and lipoproteins will also be characterized. Project 6 will utilize the mouse model to analyze the genes for trans-acting factors regulating cholesterol biosynthesis. These genes will be characterized, mapped, and isolated, and the hypothesis that alleles of HMG-CoA reductase or HMG-CoA synthase are associated with altered plasma cholesterol levels in humans will be tested. In Project 7 the factors that bind to the promoters for the rat genes HMG-CoA reductase, HMG-CoA synthase, and CR-39 will be isolated, and their role in the control of transcription and coordinate regulation of these genes determined. Other studies will seek to understand the marked differences noted among adjacent normal rat hepatocytes for the expression of the key cholesterogenic enzymes. This Program Project presents an integrated approach to the problem of atherosclerosis utilizing biochemical, cell biology, genetic, molecular biology, and state-of-the-art ultrastructural strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL030568-09
Application #
3098201
Study Section
Heart, Lung, and Blood Research Review Committee B (HLBB)
Project Start
1983-07-01
Project End
1993-06-30
Budget Start
1991-07-29
Budget End
1992-06-30
Support Year
9
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Wang, Bo; Rong, Xin; Palladino, Elisa N D et al. (2018) Phospholipid Remodeling and Cholesterol Availability Regulate Intestinal Stemness and Tumorigenesis. Cell Stem Cell 22:206-220.e4
Kasahara, Kazuyuki; Krautkramer, Kimberly A; Org, Elin et al. (2018) Interactions between Roseburia intestinalis and diet modulate atherogenesis in a murine model. Nat Microbiol 3:1461-1471
Lang, Jennifer M; Pan, Calvin; Cantor, Rita M et al. (2018) Impact of Individual Traits, Saturated Fat, and Protein Source on the Gut Microbiome. MBio 9:
McDonald, Austin I; Shirali, Aditya S; Aragón, Raquel et al. (2018) Endothelial Regeneration of Large Vessels Is a Biphasic Process Driven by Local Cells with Distinct Proliferative Capacities. Cell Stem Cell 23:210-225.e6
Roberts, Adam B; Gu, Xiaodong; Buffa, Jennifer A et al. (2018) Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med 24:1407-1417
Zhu, W; Buffa, J A; Wang, Z et al. (2018) Flavin monooxygenase 3, the host hepatic enzyme in the metaorganismal trimethylamine N-oxide-generating pathway, modulates platelet responsiveness and thrombosis risk. J Thromb Haemost 16:1857-1872
Olde Loohuis, Loes M; Mangul, Serghei; Ori, Anil P S et al. (2018) Transcriptome analysis in whole blood reveals increased microbial diversity in schizophrenia. Transl Psychiatry 8:96
Mukherjee, Pallavi; Hough, Greg; Chattopadhyay, Arnab et al. (2018) Role of enterocyte stearoyl-Co-A desaturase-1 in LDLR-null mice. J Lipid Res 59:1818-1840
Orozco, Luz D; Farrell, Colin; Hale, Christopher et al. (2018) Epigenome-wide association in adipose tissue from the METSIM cohort. Hum Mol Genet 27:1830-1846
Erbilgin, Ayca; Seldin, Marcus M; Wu, Xiuju et al. (2018) Transcription Factor Zhx2 Deficiency Reduces Atherosclerosis and Promotes Macrophage Apoptosis in Mice. Arterioscler Thromb Vasc Biol 38:2016-2027

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