Dietary sodium, neurovascular dysfunction and cerebrovascular risk

膳食钠、神经血管功能障碍和脑血管风险

• 批准号: 10298081
• 负责人: Costantino Iadecola
• 金额: $ 59.9万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10298081
• 关键词: Adhesions; Alzheimer' s Disease; Alzheimer' s disease related dementia; Automobile Driving; Bacteria; Blood Circulation; Blood Pressure; Blood capillaries; Brain; Cardiovascular Diseases; Cells; Cerebrovascular Circulation; Cerebrum; Cognition; Cognitive; Cognitive deficits; Consumption; Data; Dementia; Diet; Dietary Factors; Dietary Sodium; Down-Regulation; Endothelial Cells; Endothelium; Event; Excess Dietary Salt; Female; Flow Cytometry; Food; Functional disorder; Funding; Goals; Health; Helper-Inducer T-Lymphocyte; IL17 gene; Immune; Immunologics; Impaired cognition; Impairment; Individual; Lactobacillus; Lead; Leukocytes; Life; Light; Link; Mediating; Mediator of activation protein; Microtubule-Associated Proteins; Microvascular Dysfunction; Modeling; Molecular; Morbidity - disease rate; Mus; NOS3 gene; Neurons; Nitric Oxide; Nitric Oxide Synthase; Perfusion; Phase; Phosphorylation; Production; Public Health; Receptor Activation; Reporter; Research; Rest; Risk; Risk Factors; Role; Scaffolding Protein; Science; Small Intestines; Sodium Chloride; Source; Tauopathies; Testing; Time; Translating; adaptive immune response; aged; base; brain endothelial cell; brain health; cardiovascular risk factor; cerebrovascular; cytokine; dietary excess; dietary salt; endothelial dysfunction; experimental study; genetic regulatory protein; high salt diet; hyperphosphorylated tau; hypoperfusion; improved; in vivo; insight; link protein; male; microbiota; mortality; neurovascular; novel; novel strategies; programs; receptor; receptor downregulation; reconstitution; response; salt intake; salt sensitive; tau Proteins; tau aggregation; transcriptome sequencing; two photon microscopy

Salt consumption across the world greatly exceeds minimal requirements, and excessive dietary salt has emerged as a powerful risk factor for cognitive impairment and dementia. Increasing evidence indicates that a high salt diet (HSD) is harmful to brain health independently of the increase in blood pressure associated with HSD in salt-sensitive individuals. Unfortunately, public health efforts to curb salt intake have been futile and dietary salt consumption continues to rise worldwide. The long-term goal of this research program is to elucidate the mechanisms by which HSD is injurious to cognitive health and to develop new approaches to counteract it. During the previous funding period, we have demonstrated that HSD in mice leads to a reduction in cerebral blood flow (CBF) and cognitive impairment through suppression of endothelial nitric oxide (NO) production. These effects are mediated by a subclass of T-helper lymphocytes (Th17) in the small intestine that increases circulating levels of the cytokine IL17. IL17, in turn, leads to inhibition of endothelial NO synthase (eNOS) in cerebral endothelial cells. The resulting deficit in endothelial NO induces cognitive impairment through neuronal accumulation of hyperphosphorylated tau, a microtubule associated protein linked to Alzheimer’s disease and related dementias. However, the factors triggering the production IL17 in the gut, the cellular localization of the IL17 receptors inducing eNOS inhibition, and the role of the CBF reduction in tau accumulation remain to be established. This renewal application seeks to advance the mechanistic understanding of the cognitive effects of HSD by testing the following novel hypotheses: (a) HSD triggers distinct innate and adaptive immune responses in the gut through the microbiota, (b) the resulting increase in circulating IL17 acts on cerebral endothelial IL17 receptors to inhibit eNOS through downregulation of the eNOS regulatory protein striatin and, (c) the increased leukocyte adhesion resulting from the NO deficit leads to microvascular occlusions (capillary stalling) which promote tau accumulation in brain by reducing its microvascular clearance into the bloodstream. We will use a well-characterized model of HSD in young and old males and female mice and state-of-the- art approaches to examine gut-brain immune interactions, microvascular function, hyperphosphorylated tau, and cognitive deficits. These studies advance the understanding of the pathobiology of excessive dietary salt at the cellular and molecular levels and may lead to new approaches to mitigate its harmful effects on brain health that lead to cognitive impairment.

全世界的盐消耗大大超过了最小的要求，并且超出了饮食 盐已成为认知障碍和痴呆症的强大危险因素。增加 证据表明，高盐饮食（HSD）对大脑健康有害 盐敏感个体中与HSD相关的血压增加。不幸的是，公众 遏制盐摄入量的健康努力是徒劳的，饮食盐消费量继续增加 全世界。该研究计划的长期目标是阐明该机制 HSD对认知健康是有害的，并开发了应对它的新方法。在 以前的资金期，我们已经证明了小鼠的HSD导致脑减少 血流（CBF）和认知障碍通过抑制内皮一氧化氮（NO） 生产。这些作用是由小的T-助血淋巴细胞（Th17）的子类介导的。 肠增加了细胞因子IL17的循环水平。 IL17反过来导致抑制 脑内皮细胞中的内皮NO合酶（ENOS）。内皮的赤字 没有通过神经元积累的热磷酸化tau诱导认知障碍，A 微管相关的蛋白质与阿尔茨海默氏病和相关痴呆有关。然而， 触发肠道中生产IL17的因素，IL17接收器的细胞定位 诱导的eNOS抑制作用，CBF减少在TAU积累中的作用仍为 已确立的。此续签应用程序旨在提高对机械的理解 通过测试以下新颖假设，HSD的认知效应：（a）HSD触发不同的先天性 和通过微生物群中肠道中的自适应免疫回应，（b）导致的增加 循环IL17作用于脑内皮内皮IL17受体，可通过 eNOS调节蛋白纹状体的下调和（c）白细胞粘合剂增加 由于无赤字而导致的微血管阻塞（毛细管停滞），促进 通过将其微血管清除降低到血液中，tau在大脑中积累。我们将 在年轻人和雌性小鼠和最新 研究肠道免疫学相互作用，微血管功能的艺术方法， 高磷酸化的tau和认知缺陷。这些研究提高了对 过量饮食盐在细胞和分子水平的病理生物学，可能导致新的 减轻对大脑健康的有害影响的方法，从而导致认知障碍。