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有关的参数。雄激素调节的功能日益多样化，其中之一是它们影响细胞存活的能力，尽管参与其中的确切机制和受体(S)仍不清楚。传统上，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之一。然而，最近的证据支持雄激素也有能力引发“非基因组”行为，包括引发信号转导途径的能力。在这里，我们提供的初步数据不仅支持雄激素影响与促进细胞存活相关的细胞信号通路的能力，而且还为膜相关雄激素受体的功能提供了证据。此外，激活膜相关雄激素受体和激活细胞内雄激素受体的后果是不同的。我们推断，在一种受体类型上与另一种受体类型有相对差异的细胞或组织对雄激素或其拮抗剂的反应可能不同。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相互竞争的机制，一种是通过细胞内受体，另一种是通过经典的细胞内受体。我们的假设是，膜雄激素受体的优先激活对与细胞保护相关的参数的影响与细胞内受体激活时不同。在这项应用中，我们将在四个模拟神经元和神经胶质细胞的互补实验系统中区分激活经典受体和膜相关受体的后果。具体地说，我们将确定神经元和胶质细胞是否具有假定的膜雄激素受体的相同表达水平。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)神经元和神经胶质模型中的细胞存活。从拟议的实验中获得的结果将为雄激素的神经生物学提供新的和重要的机制细节，我们相信这些细节将与开发基于雄激素的治疗阿尔茨海默病等年龄相关疾病的新策略有关。

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.