PROGESTERONE REGULATION OF ALZHEIMER'S RELATED PATHOLOGY

描述(由申请人提供)：妇女健康倡议记忆研究的结果表明，接受激素治疗(HT)的妇女患阿尔茨海默病(AD)的风险增加，导致对激素干预的益处与危害进行了重新评估。作为重新评估的一部分，基础科学分析中发现的雌激素(E2、ET)和孕酮(P4)的有益结果与临床试验的不良结果之间的差异是显而易见的，观察性研究中ET和HT的总体积极结果与临床试验的有害结果之间的差异也是明显的。孕酮在脑老化和阿尔茨海默病计划项目旨在解决假想的这些差异的关键因素，以及解决缺乏关于脑区的孕酮(P4)活动的神经生物学知识，这些区域是认知所需的，容易受到阿尔茨海默氏症等与年龄相关的退行性疾病的影响。 我们计划的总体假设是，卵巢类固醇激素黄体酮促进大脑的分子、突触、细胞和行为可塑性，并降低其对阿尔茨海默病(AD)发展的易感性。具体地说，我们假设孕激素通过激活海马孕酮受体发挥直接作用，通过与雌激素途径相互作用发挥间接作用。我们进一步假设，生殖内分泌状态、卵巢剥离持续时间和AD相关病理的存在调节卵巢类固醇的可塑性反应。 我们设计了程序项目来研究P4在体内从分子到行为再到AD样病理加重的7个功能水平上的作用。每项建议都包含以下评估：(1)P4受体的表达；(2)P4对神经可塑性的直接影响；(3)临床上相关的孕激素与P4的可比性；(3)E2和P4对生殖内分泌状态、年龄或去卵巢时间的影响；(4)E2和P4对阿尔茨海默病三重转基因小鼠模型神经可塑性或炎症反应的调节。 我们的长期目标有三个：(1)在认知功能所需和易患阿尔茨海默病的大脑区域建立P4神经生物学的基础。(2)建立围绝经期和更年期的啮齿动物模型，为我们的研究和妇女健康领域的研究提供依据。(3)深入了解高血压和阿尔茨海默病的基础科学成果和临床试验结果之间的差异，以及观察性研究和临床试验之间的差异。

DESCRIPTION (provided by applicant): Results of the Women's Health Initiative Memory Study which indicated an increased risk of Alzheimer's disease (AD) in women treated with hormone therapy (HT) led to a reevaluation of the benefits versus harm of hormone interventions. As part of this reevaluation, disparities between the beneficial outcomes of estrogen (E2, ET) and progesterone (P4) found in basic science analyses and the adverse outcomes of clinical trials were clear as were the disparities between the generally positive outcomes of ET and HT in observational studies versus the deleterious outcomes of clinical trials. The Progesterone in Brain Aging and Alzheimer's Disease Program Project is designed to address key elements hypothesized to underlie these disparities as well as addressing the paucity of knowledge regarding the neurobiology of progesterone (P4) action in brain regions required for cognition and vulnerable to age associated degenerative disease such as Alzheimer's. The over arching hypothesis of our program is that the ovarian steroid hormone progesterone promotes the brain's molecular, synaptic, cellular, and behavioral plasticity and reduces its vulnerability to the development of Alzheimer's disease (AD). Specifically, we hypothesize that progesterone has direct effects via activation of progesterone receptors in hippocampus and indirect effects via interaction with estrogen pathways. We further hypothesize that the reproductive endocrine status, duration of ovariprivation and presence of AD related pathology regulates the plasticity response to ovarian steroids. We have designed the Program Project to investigate P4 action at 7 levels of function from molecular to behavioral to exacerbation of AD-like pathology in vivo. Embedded in each proposal is an assessment of: (1) P4 receptor expression; (2) direct effect of P4 on neural plasticity; (3) clinically relevant progestins for their comparability to P4; (3) change in response to E2 and P4 with reproductive endocrine status, age or duration of ovariprivation and (4) E2 and P4 regulation of neural plasticity or inflammatory responses in a triple transgenic mouse model of Alzheimer's disease. Our long-term goals are three fold: (1) To establish a foundation of P4 neurobiology in brain regions required for cognitive function and vulnerable to Alzheimer's disease. (2) To develop rodent models of human perimenopause and menopause for both our investigations and those within the field of women's health. (3) To provide insights into the basis of disparities between basic science outcomes and clinical trial outcomes as well as the disparities between observational studies and clinical trials of HT and AD.