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Role of PPARG the PPARG Target Gene RBP7 in the Endothelium

PPARG 的作用 PPARG 靶基因 RBP7 在内皮细胞中的作用

基本信息

批准号：
9249635
负责人：
Curt Daniel Sigmund
金额：
$ 61.64万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9249635
关键词：
Adipose tissue All-Trans-Retinol Anti-Inflammatory Agents Anti-inflammatory Antioxidants Aorta Binding Biological Assay Biology Blood Vessels CRISPR/Cas technology Cardiovascular Diseases Cardiovascular system Carotid Arteries Cell Nucleus Cells Cellular biology Cerebrovascular Circulation Complement Data Development Dominant-Negative Mutation Endothelial Cells Endothelium Exhibits Family Functional disorder Gene Expression Gene Expression Profiling Gene Targeting Genes Genetic Genetic Transcription High Fat Diet Human Hypertension Impairment Knock-in Mouse Knock-out Laboratories LacZ Genes Ligand Binding Ligands Lipids Mediating Molecular Monitor Mus Mutation Nitric Oxide Nuclear Translocation Oxidation-Reduction Oxidative Stress PPAR alpha PPAR delta PPAR gamma PPARG gene Pathway interactions Phenotype Physiology Play RNA Interference RXR Reactive Oxygen Species Regulation Reporting Research Personnel Retinol Binding Proteins Risk Factors Role Signal Transduction Stress Superoxides Techniques Testing Transcriptional Regulation Transgenic Mice Vasomotor adiponectin basilar artery cardiovascular risk factor early onset efficacy testing endothelial dysfunction fatty acid-binding proteins genome editing innovation insulin sensitivity lipid transport mutant novel overexpression public health relevance response rosiglitazone selective expression transcription factor transcriptome sequencing vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): PPARγ is a ligand activated transcription factor best known for its role in regulating insulin sensitivity and adipose tissue development and expansion. There is now convincing evidence to support an important beneficial role for endothelial PPARγ in the regulation of endothelial function. However, little is known about the transcriptional targets for PPARγ, how PPARγ selectively activates some targets over others, and their mechanisms of action in the endothelium. Selective expression of a dominant negative mutant of PPARγ in the endothelium (E-V290M) has no effect on endothelial function in aorta, carotid or basilar arteries in young transgenic mice at baseline, but induces severe dysfunction if the mice are challenged by a high fat diet, Ang-II, or are old. The cerebral circulation is particularly sensitive to oxidative stress in response to the interference with PPARγ signaling. Conversely, increased expression of wildtype PPARγ specifically in the endothelium (E- PPARγ-WT) reduced vasoconstriction to Ang-II. These data strongly suggest that PPARγ plays a protective role in the endothelium under stressed conditions, and the dysfunction resulting from PPARγ impairment is caused by oxidative stress. We identified retinol-binding protein 7 (RBP7) as a PPARγ target gene in the endothelium. RBP7 is an intracellular retinol binding protein belonging to the family of intracellular lipid and fatty acid-binding proteins. Expression of RBP7 is endothelial cell-specific. RBP7-deficient mice exhibit the same high fat diet-induced and Ang-II-induced phenotype as E-V290M mice which selectively express a dominant negative mutant of PPARγ in the endothelium. This led us to consider the innovative concept that the beneficial effects of PPARγ in the endothelium may be mediated by RBP7. Intracellular lipid and fatty acid binding proteins have been reported to bind ligands which activate other ligand activated transcription factors. Thus conceptually, we hypothesize that PPARγ and RBP7 may form a transcriptional regulatory loop (or hub) in endothelial cells, which is required to support an anti oxidant state and when impaired induces a pro-oxidant state. We will examine this concept in two Specific Aims. Specific Aim 1 will test the hypotheses that a) the beneficial effects of wildtype PPARγ over-expression in the endothelium require RBP7, b) that the effects of RBP7 are mediated by its retinol-binding and lipid transport activity, and c) RBP7 is required for the PPARγ- mediated anti-oxidant response, including the expression and function of endothelial adiponectin. Specific Aim 2 will evaluate the molecular mechanisms by which RBP7 regulates PPARγ transcriptional activity by testing the hypothesis that RBP7 with its intrinsic retinol binding and nuclear translocation activity is required for transcriptional activity of PPARγ.