Role of cofactors in nuclear hormone receptor function.

辅因子在核激素受体功能中的作用。

• 批准号: 8010061
• 负责人: Martin L. Privalsky
• 金额: $ 3.4万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8010061
• 关键词: Address; Binding; Biological; Biological Process; Boxing; Cell Proliferation; Complex; Defect; Disease; Endocrine; Endocrine System Diseases; Estrogen Receptors; Exhibits; Gene Targeting; Genetic Transcription; Goals; Homeostasis; Hormones; Human; Individual; Investigation; Knowledge; Lead; Lesion; Ligands; Mediating; Messenger RNA; Modeling; Molecular; N-terminal; Normal Cell; Nuclear Hormone Receptors; Nuclear Receptors; Phosphorylation; Phosphotransferases; Physiology; Process; Property; Protein Isoforms; Proteins; RNA Splicing; Recruitment Activity; Repression; Reproduction; Research; Research Personnel; Retinoids; Role; Series; Signal Transduction; Specificity; Steroids; Thyroid Hormone Receptor; Thyroid Hormone Receptor beta 1; Thyroid Hormones; Tissues; Touch sensation; Variant; adipocyte differentiation; cofactor; gene repression; human NCOR1 protein; improved; neoplastic; programs; receptor; receptor function; research study; response; transcription factor

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.

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共激活蛋白，它们与核受体物理结合，招募额外的蛋白质，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辅阻遏物和共激活物募集或功能的变化来体现其影响。我们建议继续研究核受体的作用是如何通过这些共调节因子介导的。我们将解决 5 个广泛问题的具体方面： 具体目标 1. 同一核受体的其他密切相关亚型如何表现出截然不同的转录特性：阐明甲状腺激素受体 β 1 和 β 2 不同的转录特性。 具体目标 2. SMRT 和 N-CoR 中新识别的 N 端受体相互作用结构域 (nRID) 如何促进这些受体的作用 辅阻遏物？具体目标 3. 磷酸化如何调节辅阻遏物复合物的组成和转录调控特性？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调节正常生理机能的理解，并提高我们对核心调节器功能异常如何导致疾病的了解。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。他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。