Impact of estradiol on vascular health and subsequent implications for cognitive aging.

雌二醇对血管健康的影响以及随后对认知衰老的影响。

• 批准号: 10579246
• 负责人: Sarah H. Lindsey
• 金额: $ 40.25万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579246
• 关键词: Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Angiotensin II; Animal Model; Antihypertensive Agents; Attenuated; Blood Pressure; Blood Vessels; Brain; Cardiovascular Diseases; Cardiovascular system; Chronology; Cognition; Cognitive; Cognitive aging; Collaborations; Complement; Development; Disease; Disease Progression; Early Diagnosis; Enrollment; Estradiol; Estrogen Receptor alpha; Estrogen Receptors; Estrogen decline; Estrogens; Female; GPER gene; Genetic; Goals; Health; Hormones; Hypertension; Impaired cognition; Knowledge; Laboratories; Laboratory Finding; Lead; Life; Long-Evans Rats; Luciferases; Menopause; Methods; Modeling; Molecular; Monitor; Mus; Nurses' Health Study; Organ; Ovariectomy; Perimenopause; Pharmaceutical Preparations; Pharmacology; Postmenopause; Publications; Regulation; Research Personnel; Research Project Grants; Resolution; Rodent Model; Role; Signal Pathway; Techniques; Time; Transcript; Transgenic Mice; Transgenic Organisms; Vascular Dementia; Vertebral column; Woman; Women' s Health; arterial stiffness; blood damage; cardiometabolism; cardiovascular disorder prevention; cardiovascular effects; cognitive function; dementia risk; design; experimental study; grasp; hormone therapy; improved; in vivo; innovation; menopausal hormone therapy; middle age; mouse model; neurovascular coupling; novel; older patient; pre-clinical; programs; protective effect; receptor; receptor expression; receptor function; response; ultrasound

Project 3 Summary An unresolved and important question is whether estrogen’s protective effects on the brain and cognition are attenuated or reversed during diseases such as hypertension. The goal of our overall Program Project is to address this critical gap using preclinical rodent models of healthy and unhealthy aging to understand estrogen’s impact on female cognitive aging. The experiments proposed in Project 3 contribute to this goal by comparing the impact of estrogen on vascular health in models of healthy versus unhealthy aging and complement the other Research Projects in both concept and approach. Our overall hypothesis is that cardiovascular disease alters the estrogen receptor profile, disrupting the integration of estrogen’s molecular signaling pathways and attenuating estrogen’s cardiovascular effects and downstream protection from Alzheimer’s disease and vascular dementia. Aim 1 will determine the impact of cardiovascular disease on the vascular response to hormone therapy. This aim utilizes the same middle-aged Long-Evans rat model of postmenopausal hypertension and cognitive decline as Project 1 led by Dr. Jill Daniel and builds upon our previous co-authored publication. Aim 2 will establish whether altered estrogen receptor expression impacts the response to estrogen. These experiments utilize transgenic ERE-luciferase mice along with mice lacking either ERα or GPER to grasp how cardiovascular disease alters each of these signaling pathways to reduce estrogen’s protective effects. Aim 3 will assess the impact of hypertension versus arterial stiffness on female cognition, dendritic plasticity, and neurovascular coupling and determine which antihypertensive provides the greatest protection to the brain. This aim was designed in collaboration with Co- Investigator Dr. Ricardo Mostany and utilizes his Thy-1 mouse line to directly assess central mechanisms that are associated with cognitive decline. The successful completion of the aims proposed in Project 3 will address critical gaps in our knowledge on the impact of menopausal hormone therapy, enable the development of novel methods for early detection and prevention of cardiovascular disease-induced cognitive decline, and provide innovative strategies for improving menopausal hormone pharmacology to protect from Alzheimer’s disease and vascular dementia.

项目3总结 一个尚未解决的重要问题是雌激素对大脑和认知的保护作用是否有效？ 我们整个计划项目的目标是在高血压等疾病期间减弱或逆转。 使用健康和不健康衰老的临床前啮齿动物模型来解决这一关键差距 雌激素对女性认知衰老的影响项目 3 中提出的实验有助于实现这一目标。 比较健康衰老模型和不健康衰老模型中雌激素对血管健康的影响， 我们的总体假设是 心血管疾病会改变雌激素受体的分布，破坏雌激素的整合 分子信号通路和减弱雌激素的心血管作用及其下游 预防阿尔茨海默病和血管性痴呆的目标 1 将决定其影响。 心血管疾病对血管激素治疗的反应这一目标同样适用于中年人。 Jill Daniel 博士领导的项目 1 的绝经后高血压和认知能力下降的 Long-Evans 大鼠模型 并以我们之前共同撰写的出版物为基础，目标 2 将确定雌激素受体是否发生改变。 表达影响对雌激素的反应这些实验利用转基因ERE-荧光素酶小鼠。 使用缺乏 ERα 或 GPER 的小鼠来了解心血管疾病如何改变这些信号传导 目标 3 将评估高血压与动脉粥样硬化的影响。 刚性对女性认知、树突可塑性和神经血管耦合的影响，并确定哪些 抗高血压药物为大脑提供了最大的保护。这一目标是与 Co- 合作设计的。 研究员 Ricardo Mostany 博士利用他的 Thy-1 小鼠系直接评估中枢机制 与认知能力下降有关。项目 3 中提出的目标的成功完成将解决这些问题。 我们对更年期激素治疗影响的认识存在重大差距，这使得新药的开发成为可能 早期发现和预防心血管疾病引起的认知能力下降的方法，并提供 改善更年期激素药理学以预防阿尔茨海默病的创新策略 和血管性痴呆。