REGULATORY MECHANISMS OF SRC FAMILY COACTIVATION IN ADIPOGENESIS

类固醇受体调节与新陈代谢、发育、 和繁衍。核受体通常由配体激活，并重新定位到特定的DMA 靶基因启动子上的结合位点，在那里它们积累了一系列辅助激活因子(或辅助抑制因子)， 执行调节基因表达所需的一系列转录亚步。SRC/p160 共同激活者家族似乎在后一方面发挥了基本作用。我们假设NRS和 它们伴随的辅助激活因子已演变为脂肪细胞发育的主要调节因子和 脂肪细胞和其他代谢组织中的代谢途径。 为了阐明这些控制脂肪和碳水化合物代谢的途径，我们计划 研究SRC家族的遗传、结构、调节和代谢功能 细胞提取物、细胞和动物体内的共激活剂。具体目标1：SRC-3靶基因的定义 脂肪细胞分化的调控及SRC-3在脂肪中功能的表观遗传调控研究 细胞。具体目的2：研究SRC-3在脂肪细胞分化过程中的蛋白稳定作用。 特定目标3：脂肪细胞SRC-辅活化子复合体的特性。具体目标4：研究 三个p160 SRC家族成员和COUPTF-II各自在以下方面的具体贡献 负责脂肪形成过程的事件。 为了完成这些任务，我们将使用综合方法论的方法来证明我们的假设 它使用了细胞生物学，生物化学，物理化学，物理化学， 显微镜、核酸和转基因生物学、遗传学和动物生理学。此信息将 使我们更好地了解辅活子生物学对脂肪细胞功能和 应该发现新的干预点，这将有助于新陈代谢疗法的设计 人类的疾病。

Steroid receptors regulate the expression of a myriad of target genes involved in metabolism, development, and reproduction. Nuclear receptors (NRs) are activated, usually by ligands, and relocate to specific DMA binding sites at target gene promoters where they accumulate an array of coactivators (or corepressors) that carry out the series of transcriptional substeps required for modulating gene expression. The SRC/p160 family of coactivators appears to play a fundamental role in this latter regard. We hypothesize that NRs and their attendant coactivators have evolved as the primary regulators of adipocyte devevelopment and of metabolic pathways in fat cells and other metabolic tissues. Toward the goal of elucidating these pathways that control lipid and carbohydrate metabolism, we plan to carry out investigations of the genetic, structural, regulatory and metabolic functions of SRC family coactivators in cell extracts, in cells and in animals. Specific Aim 1: Definition of SRC-3 target genes regulated during adipocyte differentiation and study of the epigenetic regulators of SRC-3 function in fat cells. Specific Aim 2: Study of the role of protein stabilization of SRC-3 during adipocyte differentiation. Specific Aim 3: Characterization of adipocyte SRC-coactivator complexes. Specific Aim 4: Study of the specific contribution of each of the three p160 SRC family members and COUPTF-II in the cascade of events responsible for the adipogenic process. To accomplish these tasks, we will employ an integrative methodological approach to prove our hypothesis which uses the technoloigies of cellular biology, biochemistry, physical chemistry, physical chemistry, microscopy, nucleic acid and transgenic biology, and genetics and animal physiology. This information will lead to a much greater understanding of the contributions of coactivator biology to adipocyte function and should uncover new intervention points that would aid in the design of novel therapies for metabolic disorders in humans.