Age-related Hypertension and Vascular Cognitive Impairment

年龄相关性高血压和血管性认知障碍

基本信息

批准号：
10558579
负责人：
David H Farb
金额：
$ 80.27万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10558579
关键词：
Address Adult Age Aging Alzheimer&apos s Disease Angiotensin II Type 1 Receptor Blockers Attenuated Blood - brain barrier anatomy Blood Pressure Blood brain barrier dysfunction Cardiovascular system Cerebral small vessel disease Cerebrum Clinical Cognition Data Dementia Development Electrophysiology (science)Event Exhibits Female Functional disorder Goals Gonadal Hormones Hemorrhage Hippocampus Hypertension Impaired cognition Incidence Link Maintenance Modeling Neurocognitive Neuronal Dysfunction Neurons Neurosciences Outcome Ovariectomy Play Postmenopause Prevalence Public Health Rattus Receptor, Angiotensin, Type 1 Research Risk Factors Rodent Role Source Specialist Sprague-Dawley Rats Testing Vascular Cognitive Impairment Woman age related aged antagonist blood pressure reduction blood pressure regulation cognitive function cost design female sex hormone healthy aging hypertensive improved innovation insight male mild cognitive impairment multidisciplinary neural circuit neuroinflammation neuroprotection neuroregulation new therapeutic target normal aging novel paraventricular nucleus sex vascular injury

项目摘要

ABSTRACT Hypertension is a key risk factor for the development of cerebral small vessel disease, the foremost source of vascular cognitive impairment which is the second most common cause of dementia after Alzheimer’s disease. There is increasing evidence that blood brain barrier dysfunction and neuroinflammation play a pivotal role in the pathophysiology of hypertension and contribute to the development of vascular cognitive impairment. While Angiotensin II Type 1 receptor antagonists are first line therapy to treat hypertension they have recently been demonstrated to improve neurocognitive function. Given the annual cost of dementia in the US is expected to double by 2040, the prevalence of hypertension rises from 46% of U.S. adults aged 20-44 to >78% of U.S. adults above the age of 65, and that hypertension incidence increases dramatically post-menopause there is a critical public health need for a greater understanding of the mechanistic link(s) between sex, age-dependent hypertension and vascular cognitive impairment. This application will test the global hypothesis that normal aging evokes sex-dependent hypertension that drives central microvascular injury and neuroinflammation to cause vascular cognitive impairment which can be ameliorated by Angiotensin II Type 1 receptor antagonism. Our Aims will be conducted in male and female 3-, 8-, and 16-month-old Sprague-Dawley rats (model of normal aging). The following Specific Aims will test this hypothesis: Specific Aim 1: Hypothalamic PVN blood brain barrier dysfunction and neuroinflammation contribute to age-dependent hypertension via a reversible sex-dependent Angiotensin II Type 1 receptor mechanism. Specific Aim 2: Age-dependent hypertension evoked hippocampal microvascular injury and neural circuit dysfunction drives vascular cognitive impairment via a reversible sex-dependent Angiotensin II Type 1 receptor mechanism. Our innovative approach is directly aligned with NIA Stratetgic Goals that address Alzheimer's disease and its related dementias and is designed to provide novel insights into the basic mechanisms contributing to sex- and age-dependent hypertension- driven vascular cognitive impairment and fully meets the intent of PAR-19-070 and NOT-AG-20-038. Specific Aim 1 will establish that hypothalamic PVN blood brain barrier dysfunction and neuroinflammation contribute to the development of age-dependent hypertension, which drives vascular cognitive impairment, via a reversible sex-dependent Angiotensin II Type 1 receptor mechanism. Specific Aim 2 will establish that age-dependent hypertension evoked hippocampal microvascular injury and neural circuit dysfunction drives vascular cognitive impairment via a reversible sex-dependent Angiotensin II Type 1 receptor mechanism. Our innovative approach will directly investigate the sex dependent mechanistic sequelae of events and underlying neural dysfunction in both the PVN and hippocampus that is associated with, and perhaps contributing to, age- dependent hypertension-driven vascular cognitive impairment.

抽象的高血压是脑小血管疾病发展的关键危险因素，脑小血管疾病是脑小血管疾病的首要来源。血管性认知障碍是继阿尔茨海默病之后导致痴呆的第二常见原因。越来越多的证据表明血脑屏障功能障碍和神经炎症在高血压的病理生理学并有助于血管性认知障碍的发展。血管紧张素 II 1 型受体拮抗剂是治疗高血压的一线疗法考虑到美国每年因痴呆症造成的费用预计将增加到 2040 年，美国 20-44 岁成年人的高血压患病率将增加一倍，从 46% 上升到 78% 以上。 65岁以上的成年人，绝经后高血压发病率急剧增加关键的公共卫生需要更好地了解性别、年龄依赖性之间的机制联系高血压和血管性认知障碍该应用程序将测试正常的总体假设。衰老会引起性别依赖性高血压，从而导致中枢微血管损伤和神经炎症引起血管性认知障碍，可通过血管紧张素 II 1 型受体拮抗剂改善。我们的目标将在 3、8 和 16 个月大的雄性和雌性 Sprague-Dawley 大鼠（模型）中进行以下具体目标将检验这一假设：具体目标 1：下丘脑 PVN 血液脑屏障功能障碍和神经炎症通过可逆性机制导致年龄依赖性高血压性别依赖性血管紧张素 II 1 型受体机制具体目标 2：年龄依赖性高血压。诱发海马微血管损伤和神经回路功能障碍导致血管性认知障碍通过可逆的性别依赖性血管紧张素 II 1 型受体机制，我们的创新方法是直接的。与解决阿尔茨海默病及其相关痴呆症的 NIA 战略目标保持一致，并设计为性别和年龄依赖性高血压的基本机制提供新的见解驱动的血管性认知障碍，完全符合 PAR-19-070 和 NOT-AG-20-038 的特定意图。目标 1 将确定下丘脑 PVN 血脑屏障功能障碍和神经炎症会导致年龄依赖性高血压的发展，通过可逆性机制导致血管性认知障碍性别依赖性血管紧张素 II 1 型受体机制特定目标 2 将建立年龄依赖性。高血压诱发海马微血管损伤，神经回路功能障碍驱动血管认知通过可逆的性别依赖性血管紧张素 II 1 型受体机制来抑制损伤。该方法将直接研究事件的性别依赖性机制后遗症和潜在的神经 PVN 和海马体功能障碍与年龄有关，并且可能是其原因之一依赖性高血压驱动的血管性认知障碍。