Membrane Androgen Receptors in Neuroprotection

描述（由申请人提供）：雄激素的影响远远超过与生殖功能相关的参数。在雄激素调节的日益多样化的功能中，它们能够影响细胞存活，尽管所涉及的确切机制和受体仍不清楚。经典地，雄激素如双氢睾酮（DHT）的作用归因于通过雄激素受体调节基因转录，雄激素受体是核类固醇激素受体超家族的成员。然而，最近的证据支持雄激素的能力，引发“非基因组”的行动，以及，包括引发信号转导途径的能力。在这里，我们提供了初步的数据，不仅支持雄激素的能力，影响细胞信号通路相关的促进细胞存活，但也提供了一个功能性膜相关的雄激素受体的证据。此外，激活膜相关雄激素受体的结果不同于激活细胞内雄激素受体。我们推断，在一种受体类型上相对于另一种受体类型具有相对差异的细胞或组织可能对雄激素或其拮抗剂产生不同的反应。因此，关于雄激素是保护性的还是破坏性的不一致的发现可能是由于存在两种竞争机制，一种通过细胞内受体，另一种通过经典的细胞内受体。我们的假设是，优先激活膜雄激素受体的影响参数与细胞内受体被激活时不同的细胞保护。在这个应用程序中，我们将区分激活经典受体与膜相关受体在四个互补的实验系统，模拟神经元和神经胶质细胞的后果。具体来说，我们将确定是否神经元和神经胶质细胞有相同水平的表达的假定膜雄激素受体。其次，我们将评估这种膜雄激素受体的激活如何影响1）与神经保护相关的信号转导，以及2）在神经元和神经胶质模型中的细胞存活。从所提出的实验中获得的结果将提供关于雄激素的神经生物学的新的和重要的机制细节，我们相信这些细节将与开发用于诸如阿尔茨海默病的年龄相关疾病的新的基于雄激素的治疗策略有关。

DESCRIPTION (provided by applicant): Androgens influence much more than parameters related to reproductive function. Among the increasingly diverse functions regulated by androgens is their ability to influence cell survival, although the precise mechanism and receptor(s) that are involved remain unclear. Classically, the effects of androgens like dihydrotestosterone (DHT) are attributed to the regulation of gene transcription through the androgen receptor, a member of the nuclear steroid hormone receptor superfamily. However, recent evidence supports the ability of androgens to elicit "non-genomic" actions as well, including the ability to elicit signal transduction pathways. Here, we provide preliminary data that not only support the ability of androgens to influence cell signaling pathways relevant to promoting cell survival, but also offer evidence for a functional membrane-associated androgen receptor. Moreover, the consequences of activating the membrane- associated androgen receptor were different from activating the intracellular androgen receptor. We infer that cells or tissue that have relative differences in one receptor type over another may respond differently to androgens or their antagonists. As such, inconsistent findings as to whether androgens are protective or damaging may be due to the existence of two competing mechanisms, one via the intracellular receptor and the other via the classical intracellular receptor. Our hypothesis is that preferential activation of the membrane androgen receptor influences parameters related to cell protection differently than when intracellular receptors are activated. In this application, we will differentiate the consequences of activating the classical receptor versus the membrane-associated receptor in four complementary experimental systems that model neurons and glia. Specifically, we will determine whether neurons and glia have the same level of expression of the putative membrane androgen receptor. Secondly, we will assess how activation of this membrane androgen receptor influences 1) signal transduction relevant to neuroprotection, and 2) cell survival, in both the neuronal and glial models. The results obtained from the proposed experiments will provide new and important mechanistic details about the neurobiology of androgens that we believe will be pertinent to the development of novel androgen-based therapeutic strategies for such age- related diseases like Alzheimer's Disease.