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:
- 金额:$ 80.27万
- 依托单位:
- 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:
- 关键词:AddressAdultAgeAgingAlzheimer&aposs DiseaseAngiotensin II Type 1 Receptor BlockersAttenuatedBlood - brain barrier anatomyBlood PressureBlood brain barrier dysfunctionCardiovascular systemCerebral small vessel diseaseCerebrumClinicalCognitionDataDementiaDevelopmentElectrophysiology (science)EventExhibitsFemaleFunctional disorderGoalsGonadal HormonesHemorrhageHippocampusHypertensionImpaired cognitionIncidenceLinkMaintenanceModelingNeurocognitiveNeuronal DysfunctionNeuronsNeurosciencesOutcomeOvariectomyPlayPostmenopausePrevalencePublic HealthRattusReceptor, Angiotensin, Type 1ResearchRisk FactorsRodentRoleSourceSpecialistSprague-Dawley RatsTestingVascular Cognitive ImpairmentWomanage relatedagedantagonistblood pressure reductionblood pressure regulationcognitive functioncostdesignfemale sex hormonehealthy aginghypertensiveimprovedinnovationinsightmalemild cognitive impairmentmultidisciplinaryneural circuitneuroinflammationneuroprotectionneuroregulationnew therapeutic targetnormal agingnovelparaventricular nucleussexvascular 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.
摘要
高血压是脑小血管疾病发展的关键危险因素,
血管性认知障碍,这是继阿尔茨海默氏病之后第二大常见的痴呆症原因。
越来越多的证据表明,血脑屏障功能障碍和神经炎症在脑缺血中起着关键作用。
高血压的病理生理学,并有助于血管性认知障碍的发展。而
血管紧张素II 1型受体拮抗剂是治疗高血压的一线疗法,
改善神经认知功能。考虑到美国每年治疗痴呆症的费用,
到2040年,高血压的患病率将从20-44岁美国成年人的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、年龄依赖性和性别之间的机械联系,
高血压和血管性认知障碍。这个应用程序将测试的全球假设,正常
衰老引起性依赖性高血压,导致中枢微血管损伤和神经炎症,
引起血管性认知障碍,其可通过血管紧张素II 1型受体拮抗剂改善。
我们的目的将在雄性和雌性3月龄、8月龄和16月龄的Sprague-Dawley大鼠(哺乳动物模型)中进行。
正常老化)。以下特定目的将检验该假设:特定目的1:下丘脑PVN血液
脑屏障功能障碍和神经炎症通过可逆性高血压,
性别依赖性血管紧张素II 1型受体机制。具体目标2:血压依赖性高血压
诱发性海马微血管损伤和神经回路功能障碍驱动血管性认知障碍
通过可逆的性别依赖性血管紧张素II 1型受体机制。我们的创新方法直接
与NIA治疗阿尔茨海默病及其相关痴呆症的目标一致,
提供新的见解的基本机制,有助于性别和年龄依赖性高血压-
驱动的血管性认知障碍,完全符合PAR-19-070和NOT-AG-20-038的目的。具体
目的1将建立下丘脑PVN血脑屏障功能障碍和神经炎症有助于
年龄依赖性高血压的发展,通过可逆的
性别依赖性血管紧张素II 1型受体机制。具体目标2将确定年龄依赖性
高血压诱发的海马微血管损伤和神经回路功能障碍驱动血管认知
通过可逆性性别依赖性血管紧张素II 1型受体机制的损伤。我们的创新
方法将直接调查事件的性别依赖性机制后遗症和潜在的神经
PVN和海马两者的功能障碍与年龄相关,并且可能导致年龄-
依赖性高血压导致的血管性认知障碍
项目成果
期刊论文数量(0)
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David H Farb其他文献
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{{ truncateString('David H Farb', 18)}}的其他基金
Age-related Hypertension and Vascular Cognitive Impairment
年龄相关性高血压和血管性认知障碍
- 批准号:
10375761 - 财政年份:2022
- 资助金额:
$ 80.27万 - 项目类别:
Age-Related Changes in Neural Network Activity and Tau in a rat model of Alzheimer's Disease
阿尔茨海默病大鼠模型中神经网络活动和 Tau 蛋白与年龄相关的变化
- 批准号:
9530214 - 财政年份:2018
- 资助金额:
$ 80.27万 - 项目类别:
Neuroactive Steroids,Dopamine and Cocaine Sensitization
神经活性类固醇、多巴胺和可卡因致敏
- 批准号:
6751694 - 财政年份:2002
- 资助金额:
$ 80.27万 - 项目类别:
Neuroactive Steroids,Dopamine and Cocaine Sensitization
神经活性类固醇、多巴胺和可卡因致敏
- 批准号:
6624278 - 财政年份:2002
- 资助金额:
$ 80.27万 - 项目类别:
Neuroactive Steroids,Dopamine and Cocaine Sensitization
神经活性类固醇、多巴胺和可卡因致敏
- 批准号:
6473346 - 财政年份:2002
- 资助金额:
$ 80.27万 - 项目类别:
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