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: 10732722
• 负责人: Monica M Santisteban
• 金额: $ 23.81万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 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 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10732722
• 关键词: Acetates; Adult; Affect; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease related dementia; American Heart Association; Angiotensin II; Antihypertensive Agents; Autopsy; Behavior; 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; Human; Hypertension; IL17 gene; Immune; Immune response; Immune signaling; Impaired cognition; Impairment; Individual; Inflammatory; Knowledge; Lead; Link; Macrophage; 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 Induction; Pathology; Patients; Peripheral; Predisposition; Prevention approach; Production; Public Health; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Regulation; Renin-Angiotensin System; Risk Factors; Rodent; Rodent Model; Role; Signal Pathway; Signal Transduction; Site; Sodium Chloride; Source; Stress; T cell infiltration; T-Lymphocyte; Testing; United States National Institutes of Health; Vascular blood supply; base; burden of illness; career; cellular targeting; cerebral microvasculature; cerebrovascular lesion; clinical diagnosis; cytokine; dementia risk; dietary salt; disability; genetic approach; human model; hypertensive; insight; knock-down; middle age; mouse model; neurovascular; neurovascular unit; novel strategies; novel therapeutic intervention; novel therapeutics; pharmacologic; receptor; salt intake; salt sensitive hypertension; symposium; training opportunity; vascular cognitive impairment and dementia; 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.

项目总结 痴呆症是导致死亡和残疾的主要原因，已成为#年的主要公共卫生问题之一。 今天。高血压是痴呆症的主要危险因素，既有阿尔茨海默病(AD)，也有阿尔茨海默病 相关痴呆(ADRD)。高血压扰乱神经血管单位的功能，促进血管 功能不全，导致神经元功能障碍和认知功能障碍。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，但尚不清楚它是如何导致 与认知障碍有关。食盐激活信号通路促进白细胞介素17的产生 (IL17)，并在高血压患者中发现循环中细胞因子IL17水平升高， 增加了这种细胞因子可能参与的可能性。在这里，我们将检验这样一种假设，即 盐敏感型HTN的发生是由IL17作用于内皮细胞和血管周围的IL17受体介导的 巨噬细胞(PVM)是一种产生自由基的免疫细胞，位于血管周围空间，与 脑微血管，通过两种不同的机制：(1)循环中的IL17作用于内皮细胞而导致丢失 一氧化氮(NO)的有益作用，而(2)渗入脑膜的T细胞增加IL17在 作用于PVM以诱导氧化应激和促炎信号的脑脊液。加在一起，这些 盐敏感型HTN患者的行为可导致脑血管功能障碍和认知功能障碍。为此，我们将 首先建立小鼠神经血管和认知功能障碍之间的时间关系 盐敏性高血压。然后，我们将使用药理学和细胞特异性遗传方法来确定 在这个模型中，IL17在神经血管和认知功能障碍中的作用，并建立了什么是 白介素17在神经血管单位的细胞靶点。最后，我们将确定外围设备与中央设备的角色 T细胞在调节功能障碍中的作用，侧重于脑膜IL 17gdT细胞的相对贡献。要实现 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。 对于IL17受体A亚单位的特定条件敲除除了为我提供一个独特的 培训机会，这些研究将填补在了解HTN的机制方面的明显空白 而过量的食盐会导致认知障碍，并可能提供新的治疗方法来缓解 HTN对认知健康的破坏性影响。

项目成果

Cell autonomous role of border associated macrophages in ApoE4 neurovascular dysfunction and susceptibility to white matter injury.

边界相关巨噬细胞在 ApoE4 神经血管功能障碍和白质损伤易感性中的细胞自主作用。

• DOI: 10.21203/rs.3.rs-3222611/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Iadecola,Costantino;Anfray,Antoine;Schaeffer,Samantha;Hattori,Yorito;Santisteban,Monica;Casey,Nicole;Wang,Gang;Strickland,Michael;Zhou,Ping;Holtzman,David;Anrather,Josef;Park,Laibaik
• 通讯作者: Park,Laibaik