Ovarian Hormone Regulation of Central and Cerebrovascular Hemodynamics

卵巢激素对中枢和脑血管血流动力学的调节

• 批准号: 10312395
• 负责人: Lyndsey DuBose
• 金额: $ 6.64万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312395
• 关键词: Ovarian; Hormone; Regulation; Central; Cerebrovascular

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.

项目概要 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药物的早期作用 （例如，中央动脉僵硬）和脑内（例如，脑血流量和内皮功能减少） AD 神经病理学发展中的血管和线粒体功能障碍。更年期有关联 随着氧化应激的增加和血管老化的加速以及雌激素的丧失表明 女性可能对 AD 的发展有更多的血管贡献。本次活动的总体目标 研究项目是调查雌激素下降对血管对大脑衰老的影响的作用 女性，以及与线粒体氧化应激增加相关的潜在机制。 {在人类中}我们 将使用横断面和干预研究设计来分离雌激素缺乏对 女性脑外和脑内血管功能的变化。健康的绝经前和绝经后女性 没有认知障碍的人将接受基线血管测试。此外，绝经前还会经历 为期 12 周的性腺抑制，暂时且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。 {分离线粒体和 脑血管功能缺乏雌激素，脑小动脉取自女性 卵巢切除大鼠接受地加瑞克治疗并随机接受雌激素或安慰剂加回治疗 10- 几周。线粒体功能的脑内皮依赖性标记物和蛋白质标记物将在 孤立的脑动脉。}拟议研究的结果将为性别差异提供机制上的见解 女性 AD 风险，并可能为预防或减缓 AD 发病的未来新治疗目标提供信息 在女性中。 申请人 Lyndsey DuBose 博士接受了脑外血管贡献方面的研究生培训 爱荷华大学的人类认知老化。 DuBose 博士和她的指导团队开发了一种 培训计划以她之前的经验为基础，培养女性血管健康方面的新技能。博士。 DuBose 的培训目标是获得： 1) 临床试验设计、生物成像、高级技术方面的教学培训 生物统计学和生殖内分泌学； 2) 进行机械驱动人类的经验 临床转化研究； 3) {首次发展基本科学技能，包括测量 雌性大鼠的线粒体和血管功能}； 4）发表多篇第一作者论文并提高 她的资助写作技巧是为了成为女性心血管领域的独立临床研究员 和脑血管老化。