Our Program Project is focused on the genetic dissection of metabolic syndrome (MetSyn) in both mouse models and human populations. Our approach is, we believe, unique in its multifaceted and integrative approaches. These include a combination of genetic, genomic, biochemical, physiologic, and bioinformatic analyses. During the current grant cycle, each of the four projects has been highly productive. Project 1 has utilized traditional positional cloning as well as integrative genetics in mice to identify several novel genes affecting adiposity, lipoprotein metabolism, and insulin sensitivity. Project 2 has used linkage and association analysis of human populations to identify a number of novel genes in triglyceride and HDL metabolism. Project 3 has identified and characterized a novel gene controlling the maturation of lipases. Project 4 has carried out detailed molecular studies of the lipin family of proteins, identifying key functions in fat storage and insulin sensitivity. We now propose 4 Projects and 4 Cores. All projects are direct continuations of the present projects, as are the 4 Cores. Project 1 will focus on the integration of mouse and human gene networks for MetSyn and also address the problem of gene-by-environment interactions in MetSyn. Project 2 will further elucidate underlying mechanisms for novel genes identified in human subjects during the present cycle and use both linkage and association in large population samples to further dissect the genetic factors contributing to MetSyn. Project 3 will focus on the biology lipase maturation factor-1, in both mice and humans. Project 4 will examine the role of lipins in adipogenesis and insulin sensitivity and in statin-induced myopathy as well as new genes identified in Project 1. Each of the proposed Projects will interact significantly with each of the other Projects and all of the Cores.

Public Health Relevance

Obesity has increased dramtically in the US and many other parts of the world over recent decades particularly among the young. This will clearly result in an epidemic of MetSyn that is likely to exact a horrific toll. Our Program directly addresses the problem by analysis of the genes and pathways contributing to the clinical complications of MetSyn, therby providing a framework for the development of new therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
2P01HL028481-26A1
Application #
7941350
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Liu, Lijuan
Project Start
1997-04-01
Project End
2015-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
26
Fiscal Year
2010
Total Cost
$2,540,124
Indirect Cost
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:
Cherlin, Svetlana; Wang, Maggie Haitian; Bickeböller, Heike et al. (2018) Detecting responses to treatment with fenofibrate in pedigrees. BMC Genet 19:64
Park, Shuin; Ranjbarvaziri, Sara; Lay, Fides D et al. (2018) Genetic Regulation of Fibroblast Activation and Proliferation in Cardiac Fibrosis. Circulation 138:1224-1235
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
Lee, Jessica M; Ong, Jessica R; Vergnes, Laurent et al. (2018) Diet1, bile acid diarrhea, and FGF15/19: mouse model and human genetic variants. J Lipid Res 59:429-438
Miao, Zong; Alvarez, Marcus; Pajukanta, Päivi et al. (2018) ASElux: an ultra-fast and accurate allelic reads counter. Bioinformatics 34:1313-1320
Kurt, Zeyneb; Barrere-Cain, Rio; LaGuardia, Jonnby et al. (2018) Tissue-specific pathways and networks underlying sexual dimorphism in non-alcoholic fatty liver disease. Biol Sex Differ 9:46
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
Chella Krishnan, Karthickeyan; Kurt, Zeyneb; Barrere-Cain, Rio et al. (2018) Integration of Multi-omics Data from Mouse Diversity Panel Highlights Mitochondrial Dysfunction in Non-alcoholic Fatty Liver Disease. Cell Syst 6:103-115.e7

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