Vascular mechanisms for the effects of ovarian suppression on cognitive function

描述（由申请人提供）：Kerry Hildreth，MD是老年医学部的老年病学家和讲师。她的研究重点是心血管危险因素在认知障碍中的作用。她过去的研究调查了胰岛素抵抗在认知障碍中的机制作用，最近研究了性激素对外周血管功能的影响。本项目通过研究卵巢功能丧失对女性认知功能影响的血管机制，整合了这些领域。候选人的近期目标是加强现有的研究和专业技能，并在她尚未接受过重要培训的领域发展新技能。研究和职业发展计划旨在启动候选人的职业生涯，以实现她的长期目标，即成为临床衰老研究中成功的独立研究者，以及心血管风险和认知障碍领域的领导者。职业发展计划。研究职业发展计划的关键要素是：1）加强现有的和发展新的研究和专业技能; 2）与强大的，已建立的辅导团队定期进行互动;和3）结构化的活动（例如正式的课程，会议和研讨会）。环境，。Hildreth博士将在一个出色的环境中工作，拥有强大的机构支持，最先进的研究设施，以及将初级研究人员转变为成功的独立研究人员的令人印象深刻的记录。候选人的导师和共同导师是已建立的，资助的科学家，他们成功地指导了许多初级研究人员。候选人还将得到三位咨询导师的支持，他们在各自的研究领域具有公认的专业知识。候选人将有机会获得该机构的临床转化科学奖（CTSA）和临床转化研究中心（CTRC）以及认知科学研究所的资源。Research.本项目将研究血管功能障碍作为卵巢功能丧失对认知影响的潜在机制。该研究将与Kohrt博士的女性、衰老、代谢和运动研究一起进行，在该研究中，接近绝经的女性被随机分配到促性腺激素释放激素激动剂（GnRHa）或安慰剂的卵巢激素抑制6个月。我们将在基线和6个月时测量血管（动脉硬度和内皮功能）和认知（通过fMRI检测前额叶皮层（PFC）激活）。GnRHa治疗的受试者亚组将完成额外3个月的GnRHa+雌二醇（E2）加药，并在9个月时进行检测。我们假设GnRHa治疗将与血管和认知功能的显著下降相关，这些下降将通过E2恢复，PFC激活的变化将与血管功能的变化相关。结果将增加有关血管对认知障碍的贡献的知识，并为未来的干预研究提供初步数据，以预防或延迟认知能力下降。

DESCRIPTION (provided by applicant): Kerry Hildreth, MD is a geriatrician and instructor in the Division of Geriatric Medicine. Her research focuses on the role of cardiovascular risk factors in cognitive impairment. Her past research has investigated the mechanistic role of insulin resistance in cognitive impairment, and more recently the effects of sex hormones on peripheral vascular function. This proposed project integrates these areas by investigating vascular mechanisms underlying the effects of loss of ovarian function on cognition in women. The candidate's immediate goals are to strengthen existing research and professional skills, and to develop new skills in areas in which she has not yet received significant training. The research and career development plan are designed to launch the candidate's career toward her long-term goal of becoming a successful independent investigator in clinical aging research, and a leader in the area of cardiovascular risk and cognitive impairment. Career Development Plan. The key elements of the research career development plan are: 1) strengthening current and developing new research and professional skills; 2) regular ongoing interactions with a strong, established mentoring team; and 3) structured activities (e.g. formal coursework, conferences and seminars). Environment,. Dr. Hildreth will be working in an outstanding Environment, with strong institutional support, state- of-the-art research facilities, and an impressive track record in transitioning junior investigators into successful independent researchers. The candidate's mentor and co-mentor are established, funded scientists who have successfully mentored numerous junior investigators. The candidate will also have support from three consulting mentors with recognized expertise in their respective areas of research. The candidate will have access to the resources of the institution's Clinical Translational Sciences Award (CTSA) and Clinical Translational Research Center (CTRC), as well as the Institute of Cognitive Science. Research. This project will investigate vascular dysfunction as a potential mechanism for the effects of loss of ovarian function on cognition. The study will be done in conjunction with Dr. Kohrt's Females, Aging, Metabolism and Exercise study in which women nearing menopause are randomized to 6 months of ovarian hormone suppression with gonadotropin releasing hormone agonist (GnRHa), or placebo. We will measure vascular (arterial stiffness and endothelial function) and cognitive (prefrontal cortex (PFC) activation by fMRI) at baseline and 6 months. A subgroup of GnRHa-treated subjects will complete an additional 3 months of GnRHa with estradiol (E2) add-back with testing at 9 months. We hypothesize that GnRHa treatment will be associated with significant declines in vascular and cognitive function, that these declines will be restored with E2, and that changes in PFC activation will be associated with changes in vascular function. Results will add to knowledge about vascular contributions to cognitive impairment and generate preliminary data for future intervention studies to prevent or delay cognitive decline.