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

• 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
• 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' s Disease; Alzheimer' s disease diagnosis; Alzheimer' 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

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，已成为美国主要的公共卫生问题之一。 今天高血压是痴呆的主要危险因素，包括阿尔茨海默病（AD）和阿尔茨海默病 相关性痴呆（ADRD）高血压破坏了神经血管单位的功能， 功能不全，导致神经元功能障碍和认知障碍。盐敏感性是一个关键因素， 原发性高血压，影响大约50%的高血压患者，但其导致的原因尚不清楚 认知障碍膳食盐激活促进白细胞介素-17产生的信号通路 在高血压患者中，已经确定了细胞因子IL 17的循环水平增加， 增加了这种细胞因子可能参与的可能性。在这里，我们将测试的假设， 盐敏感性HTN的发生是由IL 17介导的，IL 17作用于内皮细胞和血管周围细胞上的IL 17受体， 巨噬细胞（PVM），位于血管周围空间的产生自由基的免疫细胞，与 脑微血管通过两种不同的机制：（1）循环IL 17作用于内皮细胞，诱导脑微血管内皮细胞减少， 一氧化氮（NO）的有益作用，而（2）T细胞浸润脑膜增加IL 17在 作用于PVM以诱导氧化应激和促炎信号传导的脑脊液。所有这些 在盐敏感性HTN中，这些作用导致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， 盐敏感性高血压然后，我们将使用药理学和细胞特异性遗传方法来确定 IL 17对该模型中神经血管和认知功能障碍的贡献，并确定 IL 17在神经血管单位中的细胞靶点。最后，我们将确定外周与中枢的作用， T细胞介导的功能障碍，重点是脑膜IL 17 gdT细胞的相对贡献。实现 为了实现这些目标，我们将使用最先进的方法来研究神经血管调节，包括遗传模型 用于IL 17受体亚基A的特异性条件性敲低。除了为我提供一个独特的 培训机会，这些研究将填补一个明显的差距，在理解的机制，HTN 和过量的饮食盐导致认知障碍，并可能提供新的治疗方法，以减轻 HTN对认知健康的破坏性影响。