Project 2 focuses on identifying key regulators that provide intrinsic protection to the endothelium during the initial stages of atherosclerosis. In particular we found that NOTCH1, a cell surface receptor and transcription factor that, based on preliminary data, prevents the onset of inflammation on arterial endothelium. NOTCH1 is constitutively expressed by the adult endothelium of large arteries in mouse and human, however, expression is reduced by dietary lipids (Western Diet or LPA) in vivo. Similarly, expression analyses of endothelial cells from 147 individual human donors, revealed differences in basal and oxidized-phospholipid (ox-PAPC) treated levels of NOTCH1 and identified a locus that was associated with the response of endothelial cells to NOTCH1 by ox-PAPC. This same locus was also associated with HDL levels in a large scale GWAS including 100,000 humans. Reduction of NOTCH1 transcripts in human endothelium in vitro or endothelial-specific genetic inactivation of Notch1 in mice triggers an inflammatory response in the absence of any additional insult. Conversely, endothelial cells with constitutive overexpression of NOTCH1 are muted to the pro-inflammatory effects of ox-PAPC, implicating that NOTCH1 is downstream of ox-PAPC, at least with respect to its pro-inflammatory effects. Studies in this project will test the hypothesis that reduction of NOTCH1 by dietary lipids contributes to the prolonged inflammation typical of atherosclerotic lesions. In addition and consistent with a role in endothelial homeostasis and suppression of inflammation, reduction of endogenous NOTCH1 levels, in the absence of ox-PAPC, results in endothelial barrier breakdown, increased permeability and leukocyte binding. Mice with genetic inactivation of Notch1 exhibit leukocyte infiltration, detachment and loss of endothelial cells from the intima. Based on these findings, the central hypothesis of this application is that NOTCH1 in the endothelium is important in maintaining an anti-inflammatory interface between blood and tissue. To test this hypothesis, we propose three specific aims: 1. To identify the mechanism by which pro-atherogenic lipids regulate NOTCH1; 2. To determine the contribution of NOTCH1 in the regulation of barrier stability; and 3. To ascertain the impact of Notch1 in atherosclerosis in animal models.

Public Health Relevance

Inflammation of the vascular wall is a well-recognized predisposing factor that initiates cardiovascular disease. Experiments outlined in Project 2 are designed to elucidate the molecular mechanisms that provide pressure to maintain homeostatic control in the inner layer of large arteries and prevent the onset of atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL030568-34
Application #
9478283
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Liu, Lijuan
Project Start
Project End
Budget Start
2018-05-01
Budget End
2019-04-30
Support Year
34
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Chattopadhyay, Arnab; Yang, Xinying; Mukherjee, Pallavi et al. (2018) Treating the Intestine with Oral ApoA-I Mimetic Tg6F Reduces Tumor Burden in Mouse Models of Metastatic Lung Cancer. Sci Rep 8:9032
Hui, Simon T; Kurt, Zeyneb; Tuominen, Iina et al. (2018) The Genetic Architecture of Diet-Induced Hepatic Fibrosis in Mice. Hepatology 68:2182-2196
Kang, Eun Yong; Lee, Cue Hyunkyu; Furlotte, Nicholas A et al. (2018) An Association Mapping Framework To Account for Potential Sex Difference in Genetic Architectures. Genetics 209:685-698
Seldin, Marcus M; Koplev, Simon; Rajbhandari, Prashant et al. (2018) A Strategy for Discovery of Endocrine Interactions with Application to Whole-Body Metabolism. Cell Metab 27:1138-1155.e6
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

Showing the most recent 10 out of 791 publications