Novel Coactivator Functions during Adipogenesis

脂肪生成过程中的新型共激活剂功能

• 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
• 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

 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(申请人提供)：肥胖和与肥胖相关的健康并发症，包括糖尿病，影响着美国相当大比例的人口，预测表明，肥胖和超重的人数未来将继续上升。由于肥胖和相关并发症造成的身体和心理社会问题，加上相关的生产力损失，医疗保健费用令人震惊。改善在肥胖和超重人群中诱导生活方式改变的策略是缓解这一问题的必要步骤，但这一方法应该得到干预措施的补充，以控制调节体重增加的生理过程。这样的干预可能包括调节脂肪形成和功能调节的小分子。这类工具的开发将取决于对调节脂肪生成和脂肪功能的生理过程进行持续的基础研究。我们提供的证据表明，PRMT5和Jmjd6这两种酶作为脂肪生成的辅助激活剂，以一种独立于其催化活性的方式推动脂肪生成。这意味着这些调节因子使用新的和未明确的机制来促进成脂分化。我们建议在全球范围内定义这些调控因子在脂肪形成中的功能，并进行结构/功能分析，以确定负责促进脂肪形成的功能的蛋白质结构域。这项工作将解决这些调控蛋白如何影响高阶和局部染色质结构，其他调控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形成的调控提供新的见解，并可能为未来可能用于治疗肥胖和肥胖相关疾病的治疗干预提供新的靶点。