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Dietary Sodium, Neurovascular Dysfunction and Cerebrovascular Risk

膳食钠、神经血管功能障碍和脑血管风险

基本信息

批准号：
10650322
负责人：
Costantino Iadecola
金额：
$ 57.41万
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：
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/10650322
关键词：
Adhesions Aging Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Automobile Driving Bacteria Blood Circulation Blood Pressure Blood Vessels 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 Human Hypertension IL17 gene Immune Immunologics Impaired cognition Impairment Individual Innate Immune Response Lactobacillus Leukocytes Life Light Link Mediating Mediator Microtubule-Associated Proteins Microvascular Dysfunction Modeling Molecular Morbidity - disease rate Mus NOS3 gene Neurons Nitric Oxide Perfusion Phase Phosphorylation Policies Production Public Health Receptor Activation Reporter Research Rest Risk Risk Factors Role Scaffolding Protein Science Small Intestines Sodium Chloride Source Stroke Tauopathies Testing Time Translating Vascular Endothelium adaptive immune response aged base blood pressure elevation brain dysfunction 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 reconstitution response salt intake salt sensitive success tau Proteins tau aggregation transcriptome sequencing two photon microscopy

项目摘要

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.

世界各地的盐摄入量大大超过了最低要求，而过度饮食