Nonclassical signaling of the androgen receptor polyproline domain

描述(由申请人提供)： 已经确定核受体的整体构象受它们所结合的配体的性质的影响，并且由此产生的构象差异使得辅因子的不同招募成为可能。尽管有这些公认的概念，但仍有待确定(A)哪些受体表面负责每种生物活动，以及(B)这些表面如何机械地发挥作用。我已经确定了一个这样的表面，位于AR N端的一段独特的Pro残基，对于AR介导的最大限度的生长和选择性雄激素靶基因的调节是必要的。 候选人的长期目标是开发治疗内分泌疾病的新方法。这项建议的主要目标是利用生物信息学和分子生物学的组合来确定AR多脯氨酸结构域的特定作用(S)和两种已识别的与这一特定表面相互作用的蛋白质。这些目标将利用杜克大学医学中心药理学和癌症生物学系以及杜克基因组科学和政策研究所内的一流研究环境来实现。为实现这些目标，提出了以下具体目标： 目的1：确定雄激素调节的生物过程中AR内多聚脯氨酸结构域的作用。 目的2：确定并验证AR及其多聚脯氨酸结构域诱导的、驱动细胞生长、迁移和肌动蛋白重组等细胞效应的特定信号通路。 目的：探讨AR多聚脯氨酸结构域及其辅因子SH3YL1和Lyn激酶基因修饰对选择性雄激素受体调节剂(SARM)活性的影响。 这项工作将提供一个明确的评估在AR生物学中的作用，并促进我们对AR信号的基本理解。这项工作的洞察力将促进基于机制的筛选，以开发具有有用的组织选择性活动的化合物，SARM。 公共卫生相关性：预计该项目将有助于开发能够选择性调节雄激素调节作用的药理学策略所需的知识库。在这些研究的结论中，我们将能够直接将特定的生物过程与特定的AR辅因子相互作用联系起来。这一新信息对AR配体的未来设计将是无价的。

DESCRIPTION (provided by applicant): It has been determined that the overall conformation of nuclear receptors is influenced by the nature of the ligand to which they bind and that the resulting differences in conformation enable the differential recruitment of cofactors. Despite these accepted concepts, it still remains to be determined (a) which receptor surfaces are responsible for each biological activity and (b) how these surfaces function mechanistically. I have identified one such surface, a unique stretch of proline residues located towards the N-terminus of AR, that is necessary for maximal AR-mediated growth and the regulation of select androgen target genes. The long-term goal of the candidate is to develop novel therapeutic approaches for endocrine maladies. The primary goal of this proposal is to use a combination of bioinformatics and molecular biology to define the specific role(s) of the AR polyproline domain and two identified proteins that interact with this specific surface. These goals will be achieved using the superb research environment at Duke University Medical Center within both the Department of Pharmacology and Cancer Biology and the Duke Institute of Genome Sciences and Policy. To accomplish these goals the following specific aims are proposed: Aim 1: Determine the role of the polyproline domain within AR in androgen-regulated biological processes. Aim 2: Identify and validate the specific signaling pathways elicited by AR and its polyproline domain that drive cellular effects such as growth, migration, and actin reorganization. Aim 3: Evaluate the impact of genetic modification of the AR polyproline domain and its cofactors, SH3YL1 and Lyn kinase, on the activity of selective androgen receptor modulators (SARMs). This work will provide a definitive assessment of the role of the polyproline domain in AR biology and advance our basic understanding of AR signaling. Insights from this work will facilitate mechanism-based screens for the development of compounds, SARMs, with useful tissue-selective activities. PUBLIC HEALTH RELEVANCE: It is anticipated this project will contribute to the knowledge base needed to develop pharmacological strategies that can selectively modulate androgen-regulated actions. At the conclusion of these studies we will be able to directly link a specific biological process to a particular AR-cofactor interaction. This new information will be invaluable for the future design of AR ligands.