TGFbeta-mediated Transcriptional Reprogramming of Mature Adipocytes in Obesity

TGFβ介导的肥胖中成熟脂肪细胞的转录重编程

基本信息

批准号：
9326420
负责人：
Evan D Rosen
金额：
$ 54.7万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9326420
关键词：
Ablation Address Adipocytes Adipose tissue Affect Area Binding Cell Culture Techniques Cells Complex Data Development Disease Event Fatty acid glycerol esters Fibrosis Functional disorder Gene Expression Gene Targeting Genes Genetic Transcription Goals Health Human Hypoxia In Vitro Inflammation Insulin Resistance Knockout Mice Lead Lipolysis Mediating Metabolic Metabolic syndrome Metabolism Modeling Molecular and Cellular Biology Mus Myofibroblast Non-Insulin-Dependent Diabetes Mellitus Nutrient Obese Mice Obesity Organ Outcome Overnutrition PPAR gamma Pathway interactions Peripheral Physiological Physiology Positioning Attribute Process Reagent Role Scheme Signal Transduction Testing Therapeutic Intervention Thermogenesis Tissues Transforming Growth Factor beta adipocyte differentiation blood glucose regulation body system cell type energy balance epigenomics feeding improved in vivo insulin sensitivity interest lipid biosynthesis novel overexpression prevent response tool transcription factor

项目摘要

Adipose tissue becomes dysfunctional in the setting of obesity, and contributes significantly to the development of insulin resistance and other features of metabolic syndrome. A large part of this is believed to result from inflammation and fibrosis. Although fibrosis has been extensively studied in other tissues, adipose tissue fibrosis is still unexplored. We have generated preliminary data that that high fat feeding alters the transcriptional and epigenomic state of mature adipocytes, reducing adipogenic gene expression and promoting the elaboration of a fibrogenic milieu usually associated with myofibroblasts. Furthermore, our data suggest a role for the transcription factors Smad3 and SRF in this process. In this application, we will use a combination of murine and human cell culture models as well as in vivo studies in mice to interrogate the role of TGFβ in adipose fibrosis, focusing on the relative contributions of two downstream transcriptional effectors: the traditional Smad2/3/4 pathway typically associated with TGFβ−mediated signaling, as well as SRF. We will focus on events that lead to reduced PPARγ action and also events that promote fibrosis, assessing how much these different outcomes influence one another. Our objective is to deconvolute the complex transcriptional events that promote adipose fibrosis and to establish whether these pathways are tractable to therapeutic intervention.

脂肪组织在肥胖症的情况下变得功能失调，并显着促进您的内代谢综合征的发育和其他组织。表达并促进与肌纤维的纤维化环境相关的，我们的数据表明，在施用中，我们的数据对转录因子Smad3和SRF的作用提出了作用。，重点是两个下游转录效应子的相对贡献：传统的SMAD2/3/4途径通常与TGFβ介导的信号传导相关，我们将重点介绍导致PPARγ动作的事件以及促进纤维化的事件评估这些不同的结果彼此影响。治疗干预。