Sex, Sex Steroids & Neuroprotection

描述(由申请人提供)： 现在人们已经认识到，雌激素和雄激素强烈地调节中枢神经系统区域的损伤，与生殖功能或性别分化完全无关。这些类固醇保护(在有限的条件下，可以加剧)神经元对缺血、炎症和免疫挑战的损伤反应。这个项目的主要目的是：1)剖析主要的哺乳动物雌激素17-雌二醇拯救实验性中风、脑缺血和多发性硬化症神经元的重要机制；2)通过了解男性对缺血敏感的表型和睾酮在这一表型中的作用，开辟新的领域。该计划有几个重要的优势。首先，具有关键专业知识的强大调查人员已被纳入该计划。我们的初步数据表明了我们方法的可行性，并展示了在基于性别的病理生物学的新领域出现重要新知识的潜力。这些研究人员是各自领域中有关神经功能在健康和疾病中的机制的领导者。我们现在将这方面的专业知识集中在性和性类固醇上，这是一个传统上只对内分泌学和生殖医学感兴趣的话题。其次，研究人员使用复杂的实验方法来评估面向机制的假说。最后，这个程序非常新颖，是为数不多的探索性类固醇如何与普遍的细胞死亡/生存途径相互作用的程序之一。目前的实验方法不是像翻译研究中通常所做的那样，最小化或排除性和性类固醇，而是最大化它们。我们的发现将阐明疾病最基本的“遗传”方面背后的机制：生物学上的性别。该计划由3个项目组成：！)可卡因苯丙胺调节转录本(CART)在雌激素介导的神经保护中的作用，2)睾酮与脑缺血，3)雌激素和睾酮对实验性自身免疫性脑脊髓炎(EAE)的神经保护作用。这些项目得到了3个核心设施的支持：1)管理；2)组织分析和3)动物模型。

DESCRIPTION (provided by applicant): It is now well recognized that estrogens and androgens strongly modulate injury in CNS regions completely unrelated to reproductive function or sexual differentiation. These steroids protect (and in restricted conditions, can exacerbate) the neuronal response to injury from ischemic, inflammatory and immunological challenges. The major aim of this program is to 1) dissect important mechanisms by which the principal mammalian estrogen, 17$ estradiol, rescues neurons from experimental stroke, cerebral ischemia and multiple sclerosis and 2) open new territory by understanding the male phenotype of ischemic sensitivity and the role of testosterone in this phenotype. The Program has several important strengths. First, strong investigators with critical expertise have been integrated in the Program. Our preliminary data indicate feasibility of our approaches and demonstrate the potential for significant new knowledge to emerge in the new area of gender-based pathobiology. The investigators are leaders in their fields concerning mechanisms of neuronal function in health and disease. We now sharply focus that expertise on sex and sex steroids, a topic traditionally found of interest only to endocrinology and reproductive medicine. Second, the investigators use sophisticated experimental approaches to evaluate mechanism-oriented hypotheses. Finally, this program is highly novel, one of few to seek out how sex steroids interact with generalized cell death/survival pathways. Instead of minimizing or excluding sex and sex steroids as is commonly done in translational research, the present experimental approach maximizes them. Our findings will elucidate the mechanisms behind a most fundamental "genetic" aspect of disease: biological sex. The Program consists of 3 projects :!) Role of Cocaine Amphetamine Regulated Transcript (CART) in Estrogen mediated Neuroprotection, 2) Testosterone and Cerebral Ischemia, 3) Neuroprotective effects of estrogen and testosterone in experimental autoimmune encephalomyelitis (EAE). These projects are supported by 3 core facilities: 1) Administration; 2) Tissue Analysis and 3) Animal Models.