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，导致重新评估激素干预的益处与危害。作为重新评估的一部分，在基础科学分析中发现的雌激素（E2，ET）和孕激素（P4）的有益结果与临床试验的不良结果之间的差异是明显的，在观察性研究中ET和HT的一般积极结果与临床试验的有害结果之间的差异也是明显的。脑老化和阿尔茨海默病计划项目中的孕激素旨在解决假设为这些差异的基础的关键因素，以及解决关于认知所需的脑区域中孕激素（P4）作用的神经生物学知识的缺乏和易受年龄相关退行性疾病（如阿尔茨海默病）的影响。 我们项目的过度假设是，卵巢类固醇激素孕酮促进大脑的分子，突触，细胞和行为可塑性，并降低其对阿尔茨海默病（AD）发展的脆弱性。具体来说，我们假设孕激素通过激活海马中的孕激素受体产生直接影响，并通过与雌激素途径的相互作用产生间接影响。我们进一步推测，生殖内分泌状态，持续时间的卵巢和存在的AD相关的病理调节卵巢类固醇的可塑性反应。 我们已经设计了程序项目，以研究P4在7个功能水平上的作用，从分子到行为到体内AD样病理的恶化。每一项建议都包括对以下方面的评估：（1）P4受体表达;（2）P4对神经可塑性的直接影响;（3）与P4相似的临床相关孕激素;（3）生殖内分泌状态对E_2、P_4的反应性改变;年龄或持续时间的卵巢和（4）E2和P4调节神经可塑性或炎症反应的三重转基因小鼠模型的阿尔茨海默氏病。 我们的长期目标有三个方面：（1）在认知功能所需的大脑区域和易患阿尔茨海默病的大脑区域建立P4神经生物学基础。(2)建立人类围绝经期和绝经期的啮齿动物模型，用于我们的研究和妇女健康领域的研究。(3)深入了解基础科学结果与临床试验结果之间的差异以及HT和AD的观察性研究与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.