Novel Coactivator Functions during Adipogenesis

脂肪生成过程中的新型共激活剂功能

基本信息

批准号：
9113191
负责人：
ANTHONY N IMBALZANO
金额：
$ 41.88万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
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：
2016-05-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9113191
关键词：
ATP Hydrolysis Address Adipose tissue Basic Science Binding Binding Proteins Cells Chromatin Chromatin Loop Chromatin Structure Complement Coupled DNA Development Diabetes Mellitus Enzymes Epigenetic Process Event Future Gene Activation Gene Expression Gene Targeting Genes Genomic DNA Health Health Care Costs Higher Order Chromatin Structure Histones Individual Intervention Investigation Life Style Mediator of activation protein Molecular Obesity Obesity associated disease Overweight PPAR gamma Physiological Processes Population Post-Translational Protein Processing Proteins RNA Binding Regulation Regulator Genes Social Problems Specific qualifier value Staging Structure Tertiary Protein Structure Therapeutic Intervention Tissues Transcription Coactivator United States Weight Gain Work arginine methyltransferase cell type chromatin remodeling gene product genetic regulatory protein improved insight lipid biosynthesis novel obesity treatment productivity loss programs protein function public health relevance small molecule therapy development tool

项目摘要

DESCRIPTION (provided by applicant): Obesity and health complications related to obesity, including diabetes, impact a significant proportion of the population in the United States, and projections indicate that the number of obese and overweight individuals will continue to rise in the future. The costs of health care due to the physical and psycho-social problems caused by obesity and related complications, coupled with the associated loss of productivity, is staggering. Improving strategies to induce lifestyle changes among the obese and overweight population is a necessary step toward alleviating this problem, but this approach should be complemented by the development of interventions to control the physiological processes regulating weight gain. Such interventions may include small molecules that modulate regulators of adipose formation and function. Development of such tools will depend upon continued basic research addressing the physiological processes regulating adipogenesis and adipose function. We provide evidence that two enzymes that function as coactivators of adipogenesis, Prmt5 and Jmjd6, drive adipogenesis in a manner that is independent of their catalytic activity. This means that these regulators employ novel and undefined mechanisms to promote adipogenic differentiation. We propose to globally define the functions of these regulators in adipogenesis and to perform structure/function analyses to identify the protein domains that are responsible for the functions that contribute to adipogenesis. The work will address how these regulatory proteins influence both higher-order and local chromatin structure, binding of other regulatory proteins to chromatin, and gene expression. The results of these studies will shed new insight into the regulation of adipogenesis and potentially provide new targets for therapeutic interventions that may be of future use for the treatment of obesity and obesity related disease.

描述（由申请人提供）：肥胖和与肥胖相关的健康并发症（包括糖尿病）影响着美国很大一部分人口，预测表明肥胖和体重超重的人数未来将继续上升。由于肥胖和相关并发症引起的身体和心理社会问题，以及相关的生产力损失，医疗保健的成本令人震惊，改善肥胖和超重人群生活方式改变的策略是缓解这一问题的必要步骤。问题，但这种方法应该通过开发控制体重增加的生理过程来补充，此类干预措施可能包括调节脂肪形成和功能的小分子，此类工具的开发将取决于针对生理学的持续基础研究。我们提供的证据表明，作为脂肪生成辅激活剂的两种酶 Prmt5 和 Jmjd6 以与其催化活性无关的方式驱动脂肪生成。我们建议在全球范围内定义这些调节因子在脂肪形成中的功能，并进行结构/功能分析，以确定负责脂肪形成功能的蛋白质结构域。这些调节蛋白如何影响高级和局部染色质结构、其他调节蛋白与染色质的结合以及基因表达，这些研究的结果将为脂肪生成的调节提供新的见解，并可能为治疗干预提供新的靶点。是未来用于治疗肥胖和肥胖相关疾病。