Project 2 (P2). Genetic modifiers of atherosclerosis and foam cell lipid droplet metabolism Jonathan Smith, Ph.D., Project Leader Project Summary/Abstract Heart disease is the number one killer of men and women in the United States. Although the incidence of cardiovascular disease deaths has declined, it still accounts for ~1 out of every 3 deaths. Coronary artery disease (CAD) due to atherosclerosis was responsible for most of these deaths. Despite increased knowledge about CAD risk factors and the availably of drugs to treat them, the CAD problem has not been solved. Large human genome wide association studies have identified many common genetic variants associated with CAD, but only a small fraction of the heritable risk has been discovered. Here we propose to perform mouse genetic and genomic studies to identify atherosclerosis modifier genes and genetic modifiers of foam cell lipid droplet metabolism, yielding insights into the mechanisms that regulate these pathways. These findings may lead to novel drug targets and therapies to prevent or treat CAD.
The first aim of the proposed studies involves identifying the responsible genes and genetic variation that give rise to the mouse atherosclerosis susceptibility loci on chromosomes 2 and 17, which we have recently independently replicated. Validation will be performed by allele replacement, the gold standard method to demonstrate a direct causal effect of genetic variation on a phenotype.
The second aim of the proposed studies involves the study of an intermediate phenotype that we discovered in atherosclerosis sensitive vs. resistant mice. We found that cholesterol ester stored in lipid droplets of macrophage foam cells is metabolized by autophagy with hydrolysis mediated by lysosomal acid lipase, such that the atherosclerosis sensitive strain has lower rates of flux through this pathway, implying that this pathway is atheroprotective. Thus, we propose to use genetic, genomic, and proteomic studies to identify the genetic variant responsible for this intermediate phenotype, and validate the causal genetic variant via allele replacement. Finally, we will probe whether the antiatherogenic effect of mTOR inhibitors in mice is mediated via an induction of foam cell autophagy.

Public Health Relevance

Project 2 (P2). Project Narrative The proposed studies address a significant health concern, coronary artery disease, and will yield insight into the mechanisms that modify atherosclerosis susceptibility. The discovery of novel pathways and proteins that regulate atherosclerosis and foam cell cholesterol ester turnover offers hope for new modes of risk assessment, prevention, and therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL029582-34
Application #
9385718
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Hasan, Ahmed a K
Project Start
Project End
Budget Start
2017-11-01
Budget End
2018-10-31
Support Year
34
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Type
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Liu, Caini; Zhu, Liang; Fukuda, Koichi et al. (2017) The flavonoid cyanidin blocks binding of the cytokine interleukin-17A to the IL-17RA subunit to alleviate inflammation in vivo. Sci Signal 10:
Aziz, Moammir H; Cui, Kui; Das, Mitali et al. (2017) The Upregulation of Integrin ?D?2 (CD11d/CD18) on Inflammatory Macrophages Promotes Macrophage Retention in Vascular Lesions and Development of Atherosclerosis. J Immunol 198:4855-4867
Arif, Abul; Terenzi, Fulvia; Potdar, Alka A et al. (2017) EPRS is a critical mTORC1-S6K1 effector that influences adiposity in mice. Nature 542:357-361
Shao, Xinrui; Chen, Siyuan; Yang, Daping et al. (2017) FGF2 cooperates with IL-17 to promote autoimmune inflammation. Sci Rep 7:7024
Arif, Abul; Jia, Jie; Halawani, Dalia et al. (2017) Experimental approaches for investigation of aminoacyl tRNA synthetase phosphorylation. Methods 113:72-82
Israel, Laura; Wang, Ying; Bulek, Katarzyna et al. (2017) Human Adaptive Immunity Rescues an Inborn Error of Innate Immunity. Cell 168:789-800.e10
Zhou, Hao; Yu, Minja; Roychowdhury, Sanjoy et al. (2017) Myeloid-MyD88 Contributes to Ethanol-Induced Liver Injury in Mice Linking Hepatocellular Death to Inflammation. Alcohol Clin Exp Res 41:719-726
Zhou, Hao; Bulek, Katarzyna; Li, Xiao et al. (2017) IRAK2 directs stimulus-dependent nuclear export of inflammatory mRNAs. Elife 6:
Arif, Abul; Yao, Peng; Terenzi, Fulvia et al. (2017) The GAIT translational control system. Wiley Interdiscip Rev RNA :
Wang, Chenhui; Zhang, Cun-Jin; Martin, Bradley N et al. (2017) IL-17 induced NOTCH1 activation in oligodendrocyte progenitor cells enhances proliferation and inflammatory gene expression. Nat Commun 8:15508

Showing the most recent 10 out of 261 publications