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

基本信息

批准号：
10548812
负责人：
Lyndsey DuBose
金额：
$ 5.53万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
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/10548812
关键词：
Accounting Acetylcholine Acute Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid deposition Antioxidants Back Basic Science Biogenesis Biometry Blood Flow Velocity Blood Vessels Cardiovascular system Central Artery Cerebrovascular Circulation Cerebrovascular system Cerebrum Chronic Chronology Clinical Clinical Trials Design Cognitive aging Cross-Sectional Studies Data Development Disease Dose Early Intervention Elderly Endothelium Estrogens Female Functional disorder Future Goals Gonadotropin Hormone Releasing Hormone Grant Health Hormone Antagonists Human Impaired cognition Impairment Individual Internal carotid artery structure Intervention Intervention Studies Iowa K-Series Research Career Programs Late Onset Alzheimer Disease Longevity Measurement Measures Mediating Menopause Mentors Mission Mitochondria Mitochondrial Proteins Morbidity - disease rate NG-Nitroarginine Methyl Ester NOS3 gene Nitric Oxide Synthetase Inhibitor Operative Surgical Procedures Ovarian hormone Oxidative Stress Pathogenesis Pathology Placebos Postmenopause Premenopause Production Proteins Publications Randomized Rattus Reactive Oxygen Species Reproductive Endocrinology Research Research Design Research Personnel Research Project Grants Research Training Risk Role Sex Differences Source System Testing Time Tissues Training Translational Research United States United States National Institutes of Health Universities Vascular Diseases Woman Women&apos s Health Writing aging brain arginine methyl ester arterial stiffness arteriole bioimaging career cerebral microvasculature cerebrovascular effective therapy experience hemodynamics hormone regulation hypoperfusion improved insight men middle age mitochondrial dysfunction mortality neuropathology new therapeutic target novel pressure prevent protein biomarkers reproductive sex skills therapeutic target translational approach translational scientist transmission process vascular contributions vascular risk factor

项目摘要

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.

项目摘要阿尔茨海默氏病（AD）是老年人发病和死亡率的主要原因影响妇女。没有有效的广告治疗方法，部分原因是 AD的病理生理尚不清楚。但是，越来越多的证据支持外脑外的早期作用（例如，中央动脉刚度）和脑内（例如，脑血流和内皮功能的减少） AD神经病理发展中的血管和线粒体功能障碍。更年期是关联的随着氧化应激的增加和加速的血管衰老，雌激素的丧失表明妇女可能对AD的发展具有增加的血管贡献。总体目标研究项目是研究下降在雌激素中的作用对脑衰老的血管贡献的作用妇女以及与线粒体氧化应激增加有关的潜在机制。 {在人类中，}我们将使用横截面和干预研究设计来隔离雌激素缺乏对女性外脑内和脑内血管功能的变化。健康，前后女性没有认知障碍，将接受基线血管测试。此外，绝经前将进行 12周的性腺抑制作用暂时和可逆地抑制了卵巢激素以调查与雌激素缺乏有关的早期血管变化。 {隔离线粒体和雌激素缺乏症的脑血管功能将从雌性中获得卵巢切除大鼠用degarelix治疗，随机接受雌激素或安慰剂添加额，以10- 几周。线粒体功能的脑内皮依赖性和蛋白质标志物将在拟议研究的孤立脑动脉。}将提供对性别差异的机械洞察力在女性的AD风险中，可能会为预防或减慢广告发作的新颖的未来治疗靶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的研究生培训爱荷华大学人类的认知衰老。 Dubose博士和她的指导团队已经开发了培训计划以她以前的经验为基础，以发展女性血管健康的新技能。博士 Dubose的培训目标是获得：1）临床试验设计中的教学培训，生物成像，高级生物统计学和生殖内分泌学； 2）进行机械驱动的人临床翻译研究； 3）{首次发展基础科学技能，包括测量雌性大鼠的线粒体和血管功能}； 4）制作了几个创作的出版物并改进她的赠款写作技巧是追求成为女性心血管的独立临床研究人员和脑血管衰老。