Role of cofactors in nuclear hormone receptor function.

描述（由申请人提供）：我们（和其他人）已经鉴定了一系列辅阻遏物和辅激活蛋白，它们与核受体物理结合，募集额外的蛋白质，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改变辅阻遏物和辅激活物的募集或功能来表现其作用。我们建议继续研究核受体的作用是如何通过这些辅助调节因子介导的。我们将讨论5个广泛问题的具体方面：具体目标1。同一核受体的密切相关的亚型如何表现出非常不同的转录特性：甲状腺激素受体β 1和β 2不同转录特性的阐明。具体目标2。SMRT和N-CoR中新识别的N-末端受体相互作用结构域（nRID）如何促进这些辅阻遏物的作用？具体目标3。辅阻遏复合物的组成和转录调控特性是如何被磷酸化调控的？具体目标4。SMRT和N-CoR的选择性mRNA剪接如何定制其分子特性？具体目标5. SMRT和N-CoR的选择性mRNA剪接如何促进其生物学功能？这些实验旨在增强我们对核受体如何介导正常生理学的理解，并提高我们对辅调节因子功能异常如何导致疾病的认识。相关性：拟议的研究将提高我们对激素在健康个体中的重要作用的认识。它们还将揭示这些功能的破坏如何导致疾病，并可能提供改善治疗的线索。

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.