Molecular Determinants of Androgen Receptor Pharmacology

描述（由申请人提供）： 直到最近，人类雄激素受体（hAR）的分子药理学被认为是相对简单的。像双氢睾酮（DHT）这样的化合物通过与受体结合并诱导受体结构的变化而起激动剂的作用。这种激活性构象变化引发了一系列事件，导致受体与靶基因内的特定DNA序列相互作用。在DNA结合状态下，受体能够与其转录调节活性所需的蛋白质和过程偶联。在这些已建立的AR作用模型中，认为拮抗剂仅通过竞争性抑制激动剂与受体的相互作用发挥作用。然而，与其它受体，特别是雌激素、孕酮和糖皮质激素受体一样，AR的药理学现在被认为更复杂，并且通常似乎是（a）受体的表达水平，（B）结合配体对受体结构的作用，（c）不同的配体-受体对结合辅激活子和辅阻遏子的能力，和（d）辅激活子和辅阻遏子在不同细胞中的相对表达水平。在这项资助中，我们提出了一系列的研究，目的是确定信息如何从AR配体流向其受体，随后流向靶基因。这将在一项具有三个特定目的的研究中完成：（1）在存在不同配体的情况下识别暴露于AR上的表面（2）定义肽结合研究所涉及的AR表面的功能意义和（3）识别与AR上功能重要表面相互作用的蛋白质。预计在这些研究结束时，我们将更好地了解目前可用的AR激动剂和拮抗剂的分子作用机制。此外，这些研究可能提出了利用AR信号通路复杂性开发选择性雄激素受体调节剂（SARM）用于治疗各种雄激素病的方法。

DESCRIPTION (provided by applicant): Until recently the molecular pharmacology of the human androgen receptor (hAR) was considered to be relatively simple. Compounds like dihydrotestosterone (DHT) functioned as agonists by binding to and inducing a change in receptor structure. This activating conformational change initiated a series of events that led to the interaction of the receptor with specific DNA sequences within target genes. In the DNA bound state the receptor was able to couple with the proteins and processes required for its transcriptional regulatory activities. In these established models of AR action, antagonists were believed to function solely by competitively inhibiting the interaction of agonists with the receptor. However, as with other receptors, notably the estrogen, progesterone and glucocorticoid receptors, the pharmacology of AR is now believed to be more complex and in general appears to be a function of (a) the expression level of the receptor, (b) the effect of the bound ligand on receptor structure, (c) the ability of differently conformed ligand-receptor pairs to engage coactivators and corepressors and (d) the relative expression level of coactivators and corepressors in different cells. In this grant we propose a series of studies with the objective of defining how information flows from an AR ligand to its receptor and subsequently to target genes. This will be accomplished in a study with three specific aims; (1) Identification of surfaces exposed on AR in the presence of different ligands (2) Definition of the functional significance of the surfaces on AR implicated by the peptide binding studies and (3) Identification of the proteins that interact with functionally important surfaces on AR. It is anticipated that at the conclusion of these studies we will have a better understanding of the molecular mechanism of action of the currently available AR agonists and antagonists. In addition these studies may suggest ways to exploit the complexity of the AR signaling pathways for the development of Selective Androgen Receptor Modulators (SARMs) for use in the treatment of a variety of androgenopathies.