Role of cofactors in nuclear hormone receptor function.

描述(申请人提供)：我们(和其他人)已经确定了一系列与核受体物理相关的辅抑制子和辅激活蛋白，招募更多的蛋白质，并帮助介导转录抑制或激活。许多影响核受体功能的信号通过辅抑制子和辅激活子募集或功能的变化来表现其影响。我们建议继续研究核受体的作用是如何通过这些共同调节因子介导的。我们将回答5个广泛问题的具体方面：特定目的1.同一核受体的其他密切相关的亚型如何表现出非常不同的转录特性：阐明甲状腺激素受体β1和β2的不同转录特性.特定目的2.新发现的SMRT和N-COR中的N-末端受体相互作用域(NRID)如何促进这些辅助抑制物的作用？具体目的3.辅阻遏子复合体的组成和转录调控特性如何受磷酸化的调节？特定目的4.SMRT和N-COR的mRNA选择性剪接如何定制其分子特性？具体目的5.SMRT和N-COR的mRNA选择性剪接对其生物学功能有何贡献？这些实验既是为了加强我们对核受体如何调节正常生理的理解，也是为了提高我们对协同调节功能异常如何导致疾病的了解。相关性：建议的研究将提高我们对荷尔蒙如何在健康个体中发挥重要作用的了解。他们还将揭示这些功能的中断如何导致疾病，并可能提供线索，从而改进治疗。

DESCRIPTION (provided by applicant): We (and others) have identified a series of corepressor and coactivator proteins that physically associate with nuclear receptors, recruit additional proteins, and help mediate transcriptional repression or activation. Many signals that impact on nuclear receptor function manifest their effects through changes in corepressor and coactivator recruitment or function. We propose to continue our research into how the actions of nuclear receptors are mediated through these coregulators. We will address specific aspects of 5 broad questions: Specific Aim 1. How can otherwise closely-related isoforms of the same nuclear receptor display very different transcriptional properties: elucidation of the divergent transcriptional properties of thyroid hormone receptors beta 1 and beta 2. Specific aim 2. How do newly recognized N-terminal receptor interaction domains (nRID) in SMRT and N- CoR contribute to the actions of these corepressors? Specific Aim 3. How are the composition and transcriptional regulatory properties of the corepressor complex regulated by phosphorylation? Specific Aim 4. How does alternative mRNA splicing of SMRT and N-CoR customize their molecular properties? Specific Aim 5. How does alternative mRNA splicing of SMRT and N-CoR contribute to their biological functions? These experiments seek both to enhance our understanding of how nuclear receptors operate in mediating normal physiology, and to improve our knowledge of how aberrations in coregulator function lead to disease. Relevance: The proposed studies will improve our knowledge of how important hormones function in healthy individuals. They also will reveal how disruptions to these functions can lead to disease, and may provide clues resulting in improved treatments.