Neuroimmune Mechanisms of Cognitive Impairment in Salt-sensitive Hypertension

盐敏感性高血压认知障碍的神经免疫机制

基本信息

批准号：
10447714
负责人：
Monica M Santisteban
金额：
$ 13.27万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
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：
2021-07-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447714
关键词：
Acetates Adult Affect Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease related dementia American Angiotensins Antihypertensive Agents Autopsy Blood Vessels Brain Cause of Death Cells Cerebrospinal Fluid Cerebrovascular Circulation Cerebrovascular Disorders Cognition Cognitive Consensus DOCA Data Dementia Deoxycorticosterone Development Elderly Endothelial Cells Essential Hypertension Excess Dietary Salt Free Radicals Functional disorder Genetic Models Goals Health Heart Human Hypertension Immune Immune response Immune signaling Impaired cognition Impairment Individual Interleukin-17 Knowledge Lead Link Mediating Meningeal Meninges Modeling National Heart, Lung, and Blood Institute National Institute of Neurological Disorders and Stroke Neuroimmunomodulation Neuronal Dysfunction Nitric Oxide Nutrient Oxidative Stress Pathology Patients Peripheral Pharmacology Predisposition Prevention therapy Production Public Health Reactive Oxygen Species Regulation Renin-Angiotensin System Risk Factors Rodent Role Signal Pathway Signal Transduction Site Sodium Chloride Source Stress T-Lymphocyte Testing United States National Institutes of Health Vascular Cognitive Impairment Vascular blood supply base burden of illness career cellular targeting cerebral microvasculature cerebrovascular clinical diagnosis cytokine dementia risk dietary salt disability genetic approach hypertensive insight knock-down macrophage middle age mouse model neurovascular neurovascular unit novel strategies novel therapeutic intervention novel therapeutics receptor salt intake salt sensitive hypertension training opportunity vascular risk factor working group

项目摘要

PROJECT SUMMARY Dementia is a major cause of death and disability and has emerged as one of the major public health issues of today. Hypertension is a leading risk factor for dementia, both Alzheimer disease (AD) but also Alzheimer disease related dementias (ADRD). Hypertension disrupts the function of the neurovascular unit and promotes vascular insufficiency, leading to neuronal dysfunction and cognitive impairment. Salt-sensitivity is a critical factor in essential hypertension, affecting approximately 50% of hypertensive individuals, but it is unknown how it leads to cognitive impairment. Dietary salt activates signaling pathways which promote production of interleukin-17 (IL17), and increasing circulating levels of the cytokine IL17 have been identified in patients with hypertension, raising the possibility that this cytokine may be involved. Here we will test the hypothesis that the harmful effects of salt-sensitive HTN are mediated by IL17 acting on IL17 receptors on both endothelial cells and perivascular macrophages (PVM), free radical-producing immune cells located in the perivascular space closely apposed to cerebral microvessels, via two distinct mechanisms: (1) circulating IL17 acts on endothelial cells to induce a loss of the beneficial effects of nitric oxide (NO), while (2) T-cells infiltrating the meninges increase IL17 in the cerebrospinal fluid which acts on PVM to induce oxidative stress and proinflammatory signaling. Together, these actions lead to cerebrovascular dysfunction and cognitive impairment in salt-sensitive HTN. To this end, we will first establish the temporal relationship between neurovascular and cognitive dysfunction in a mouse model of salt-sensitive hypertension. Then, we will use pharmacological and cell-specific genetic approaches to determine the contribution of IL17 to the neurovascular and cognitive dysfunction in this model, and establish what are the cellular targets of IL17 in the neurovascular unit. Finally, we will determine the role of peripheral versus central T-cells in mediating the dysfunction, focusing on the relative contribution of meningeal IL17gdT-cells. To achieve these goals, we will use state-of-the-art approaches to study neurovascular regulation, including genetic models for specific conditional knockdown of the IL17 receptor subunit A. In addition to providing me with a unique training opportunity, these studies will fill an obvious gap in the understanding of the mechanisms by which HTN and excessive dietary salt lead to cognitive impairment and may provide new therapeutic approaches to mitigate the damaging effects of HTN on cognitive health.

项目摘要痴呆症是死亡和残疾的主要原因，已成为今天。高血压是痴呆症的主要危险因素，两者都是阿尔茨海默氏病（AD），也是阿尔茨海默氏病相关痴呆症（ADRD）。高血压破坏神经血管单元的功能并促进血管不足，导致神经元功能障碍和认知障碍。盐敏感是关键因素基本的高血压，影响大约50％的高血压个体，但尚不清楚它如何导致认知障碍。饮食盐激活信号通路，促进白介素17的产生（IL17）以及在高血压患者中鉴定出细胞因子IL17的循环水平升高，提高了这种细胞因子可能涉及的可能性。在这里，我们将测试有害影响的假设盐敏感的HTN的介导，由作用于内皮细胞和血管上的IL17受体的IL17介导巨噬细胞（PVM），自由基产生的免疫细胞脑微血管，通过两种不同的机制：（1）循环IL17作用于内皮细胞，诱导损失一氧化氮（NO）的有益作用，而（2）T细胞浸润脑膜的脑膜增加了IL17 脑脊液作用于PVM，可诱导氧化应激和促炎信号传导。在一起，这些作用导致盐敏感HTN的脑血管功能障碍和认知障碍。为此，我们将首先在小鼠模型中建立神经血管和认知功能障碍之间的时间关系盐敏感高血压。然后，我们将使用药理和细胞特异性遗传学方法来确定在该模型中，IL17对神经血管和认知功能障碍的贡献，并确定什么是神经血管单元中IL17的细胞靶标。最后，我们将确定外围与中央的作用 T细胞介导功能障碍，重点是脑膜IL17GDT细胞的相对贡献。实现这些目标，我们将使用最先进的方法研究神经血管调节，包括遗传模型对于IL17受体亚基A的特定条件敲低。除了为我提供独特的培训机会，这些研究将填补对HTN的机制的理解的明显差距过度饮食盐会导致认知障碍，并可能提供新的治疗方法来减轻 HTN对认知健康的破坏性影响。