The intersection of lipid metabolism and inflammation in the setting of cardiovascular disease is the overall theme of our PPG. In the revised application we emphasize three specific areas within this major theme that serve as nodal points for the interactions of the component projects; i) Intestine; ii) Lipid Metabolism & Dyslipidemia; and iii) Vascular inflammation. Projects 1, 4 an 5 directly propose specific aims related to the intestine. Projects 1, 2, 4 and 5 propose specific aims related to diet-induced changes in lipid metabolism that result in dyslipidemia, or are directly affected by dyslipidemia. Additionally, Project 3 proposes specific aims related to lipid metabolism in adipose tissue. All five projects propose specific aims related to vascular inflammation. Project 1 (Fogelman) proposes two specific aims.
Aim 1 will determine the mechanisms by which unsaturated lysophosphatidic acid (LPA) and a Western diet (WD) act in the small intestine to cause dyslipidemia and inflammation.
Aim 2 will determine the mechanisms by which transgenic tomatoes expressing an apoA-I mimetic peptide (6F) ameliorates dyslipidemia and inflammation caused by intestinally-derived LPA or WD. Project 2 (Iruela-Arispe) proposes three specific aims.
Aim1 is to identify the mechanism by which pro-atherogenic lipids regulate NOTCH1.
Aim 2 is to determine the role of NOTCH1 in the regulation of barrier stability.
Aim 3 will ascertain the contribution of Notch1 to atherosclerosis using animl models. Project 3 (Bostrom) proposes two specific aims.
Aim 1 will test the hypothesis that the balance between BMP activity and inhibition regulates angiogenesis and adipogenesis in adipose tissue.
Aim 2 will investigate the impact of diabetes, lipid delivery and genetic variation on the balance between BMP activity and inhibition, and adipogenesis and angiogenesis in adipose tissue. Project 4 (Lusis/Edwards) proposes two specific aims.
Aim 1 will use the systems genetics data collected during the present cycle to model interactions in inflammation and atherosclerosis, including the involvement of Notch1, intestinal LPA and Lpcat3.
Aim 2 will test the hypothesis that the transcription factor Zhx2 is required for the survival and proliferatin of macrophage and foam cells in atherosclerotic lesions. Project 5 (Tontonoz) proposes three specific aims.
Aim 1 is to elucidate the role of Lpcat3-dependent phospholipid remodeling in lipid metabolism.
Aim 2 is to determine the role of the LXR-Lpcat3 pathway in inflammation.
Aim 3 is to determine the role of the LXR-Lpcat3 pathway in atherogenesis. Two cores will provide support to the component projects. Core A will provide administrative services. Core B will provide scientific services; analytical chemistry assays, molecular biology related services and morphology related services. The synergy between these specific aims with the support of the cores will result in a novel and comprehensive approach to understanding the intersection of lipid metabolism and inflammation. (End of Abstract) INDIVIDUAL PROJECTS AND CORE UNITS PROJECT 1:FOGELMAN PROJECT: A NOVEL ROLE OF THE SMALL INTESTINE IN DYSLIPIDEMIA AND VASCULAR INFLAMMATION (Fogelman, Alan M.)

Public Health Relevance

Cardiovascular disease remains a major health problem. This Program Project proposes novel approaches to understand fundamental mechanisms that connect the intestine, lipid metabolism and dyslipidemia to vascular inflammation, which leads to heart attack and stroke. Based on the fundamental mechanisms involved this Program also proposes novel approaches to the prevention and treatment of cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL030568-31A1
Application #
8851982
Study Section
Special Emphasis Panel (ZHL1-PPG-N (M1))
Program Officer
Liu, Lijuan
Project Start
1997-08-01
Project End
2020-04-30
Budget Start
2015-07-08
Budget End
2016-04-30
Support Year
31
Fiscal Year
2015
Total Cost
$2,310,000
Indirect Cost
$810,000
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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
Boström, Kristina I; Yao, Jiayi; Wu, Xiuju et al. (2018) Endothelial Cells May Have Tissue-Specific Origins. J Cell Biol Histol 1:
Norheim, Frode; Bjellaas, Thomas; Hui, Simon T et al. (2018) Genetic, dietary, and sex-specific regulation of hepatic ceramides and the relationship between hepatic ceramides and IR. J Lipid Res 59:1164-1174

Showing the most recent 10 out of 791 publications