Novel Coactivator Functions during Adipogenesis

 描述（由申请人提供）：肥胖症和与肥胖症相关的健康并发症，包括糖尿病，影响美国相当大比例的人口，预测表明肥胖和超重个体的数量在未来将继续上升。由于肥胖症和相关并发症造成的身体和心理社会问题，再加上相关的生产力损失，保健费用惊人。改善肥胖和超重人群的生活方式改变的策略是缓解这一问题的必要步骤，但这种方法应该辅之以干预措施的发展，以控制调节体重增加的生理过程。这种干预可能包括调节脂肪形成和功能的调节剂的小分子。这些工具的开发将取决于持续的基础研究，解决调节脂肪生成和脂肪功能的生理过程。我们提供的证据表明，两种酶的功能作为脂肪形成的共激活剂，Prmt 5和Jmjd 6，驱动脂肪形成的方式是独立的催化活性。这意味着这些调节剂采用新的和未定义的机制来促进脂肪形成分化。我们建议在全球范围内定义这些调节剂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。这项工作将解决这些调节蛋白如何影响高阶和局部染色质结构，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形成的调控提供新的见解，并可能为治疗干预提供新的靶点，这些干预可能在未来用于治疗肥胖和肥胖相关疾病。

 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.