Ovarian Hormone Regulation of Central and Cerebrovascular Hemodynamics

项目摘要 阿尔茨海默病（AD）是老年人发病和死亡的主要原因，其中老年人发病率和死亡率不成比例 影响女性。AD没有有效的治疗方法，部分原因是由于性别差异， AD的病理生理学仍不清楚。然而，越来越多的证据支持脑外的早期作用， (e.g.,中央动脉僵硬度）和脑内（例如，脑血流量和内皮功能减少） 血管和线粒体功能障碍在AD神经病理学的发展。更年期与 氧化应激增加，血管老化加速，雌激素减少，这表明， 女性可能对AD的发展具有增加的血管贡献。这个项目的总体目标是 一项研究项目是调查雌激素下降对脑血管老化的作用， 女性，以及与线粒体氧化应激增加相关的潜在机制。{In人类，}我们 将使用横断面和干预研究设计来隔离雌激素缺乏对 女性脑内外血管功能的变化。健康、绝经前和绝经后妇女 没有认知障碍的患者将接受基线血管测试。此外，绝经前将经历 12-周的性腺抑制，以暂时和可逆地抑制卵巢激素，以研究 与雌激素缺乏相关的早期血管变化。{To线粒体中孤立的变化， 雌激素缺乏的脑血管功能，脑小动脉将从女性获得 去卵巢大鼠用去甲肾上腺素治疗，并随机接受雌激素或安慰剂加药，持续10- 20天。 周脑内皮依赖性和线粒体功能的蛋白质标志物将在 孤立的大脑小动脉这项研究的结果将为性别差异提供机制性的见解 可能为预防或减缓AD发作提供新的未来治疗靶点 在女人身上。 申请人Lyndsey DuBose博士接受了脑外血管对 爱荷华州大学的人类认知老化研究。DuBose博士和她的指导团队开发了一种 培训计划，建立在她以前的经验，以发展新的技能，在妇女的血管健康。博士 DuBose的培训目标是获得：1）临床试验设计，生物成像，高级 生物统计学和生殖内分泌学; 2）在进行机械驱动的人类 临床转化研究; 3）{首次开发基本科学技能，包括测量 线粒体和血管功能的雌性大鼠}; 4）产生几个第一作者的出版物，并提高 她在追求成为一名独立的女性心血管临床研究者的过程中获得了写作技巧， 和脑血管老化。

PROJECT SUMMARY Alzheimer's disease (AD) is a major cause of morbidity and mortality in older adults that disproportionately affects women. There are no effective treatments for AD in part because sex-differences in the pathophysiology of AD remain unclear. However, increasing evidence supports the early role of extracerebral (e.g., central artery stiffness) and intracerebral (e.g., reductions in cerebral blood flow and endothelial function) vascular and mitochondrial dysfunction in the development of AD neuropathology. Menopause is associated with increased oxidative stress and accelerated vascular aging with the loss of estrogen suggesting that women may have an increased vascular contribution to the development of AD. The overall goal of this research project is to investigate the role of declines in estrogen on the vascular contribution to brain aging in women, and the underlying mechanism related to increased mitochondrial oxidative stress. {In humans,} we will use both cross-sectional and intervention study designs to isolate the effects of estrogen deficiency on changes in extra- and intra-cerebral vascular function in women. Healthy, pre- and post-menopausal women without cognitive impairment will undergo baseline vascular testing. Additionally, premenopausal will undergo 12-weeks of gonadal suppression to temporarily and reversibly suppress ovarian hormones to investigate the early vascular changes associated with estrogen deficiency. {To isolate changes in mitochondrial and cerebrovascular function with estrogen deficiency, cerebral arterioles will be obtained from female ovariectomized rats treated with degarelix and randomized to receive estrogen or placebo add-back for 10- weeks. Cerebral endothelium-dependent and protein markers of mitochondrial function will be measured in isolated cerebral arterioles.} Results of the proposed study will provide mechanistic insight into sex-differences in AD risk in women and may inform novel future therapeutic targets for preventing or slowing the onset of AD in women. The applicant, Dr. Lyndsey DuBose, received graduate training in the extracerebral vascular contributions to cognitive aging in humans at the University of Iowa. Dr. DuBose and her mentoring team have developed a training plan that builds on her previous experiences to develop new skills in women's vascular health. Dr. DuBose's training objectives are to obtain: 1) didactic training in clinical trial design, bioimaging, advanced biostatistics, and reproductive endocrinology; 2) experience in conducting mechanistically-driven human clinical translational research; 3) {develop basic science skills for the first time including the measurement of mitochondrial and vascular function in female rats}; 4) produce several first-authored publications and improve her grant writing skills in pursuit of becoming an independent clinical researcher in women's cardiovascular and cerebrovascular aging.