Mechanisms of Chronic Remote Ischemic Conditioning Induced Cerebroprotection in a VCID Model

VCID 模型中慢性远程缺血条件诱导脑保护的机制

• 批准号: 9382326
• 负责人: DAVID C. HESS
• 金额: $ 38万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9382326
• 关键词: 5' -AMP-activated protein kinase; Age; Area; Bilateral; Biological Availability; Biological Preservation; Blood Pressure; Blood Vessels; Bone Marrow; Bone Marrow Cells; Brain; Brain-Derived Neurotrophic Factor; Carotid Stenosis; Cells; Cerebral small vessel disease; Cerebrovascular Circulation; Cerebrovascular system; Chimera organism; Chronic; Cognition; Cognitive deficits; Data; Dementia; Dependence; Distant; Economic Inflation; Endocrine; Endothelium; Event; Exercise; Foundations; Goals; Growth; Human; Hypoxia; Impaired cognition; Inflammation; Intervention; Intracranial Atheroscleroses; Ischemic Brain Injury; Knock-out; Knockout Mice; Leg; Limb structure; Mediating; Modeling; Mus; NOS3 gene; National Institute of Neurological Disorders and Stroke; Nitrites; Observational Study; Organ; Pathologic; Patients; Peripheral; Phenotype; Physical Exercise; Plasma; Prevalence; Protein Kinase; Proteins; Public Health; Risk Factors; Role; Stem cells; Stroke; Testing; Translating; Vascular Dementia; Vascular remodeling; Work; abeta accumulation; acronyms; age effect; angiogenesis; arm; bench to bedside; blood vessel development; cognitive performance; conditioning; effective therapy; improved; mimetics; mouse model; nervous system disorder; neurovascular unit; novel; sex; shear stress; sound; vascular cognitive impairment and dementia; white matter damage

The prevalence of dementia is expected to triple by 2050 making it a major threat to world public health. Vascular dementia makes up 20% of dementia cases and vascular causes contribute to another 30%. These vascular contributions to cognitive impairment and dementia are known by the acronym VCID. There is no known effective treatment for VCID; however observational studies strongly suggest that physical exercise is effective at reducing progression of cognitive decline and dementia. Chronic remote ischemic conditioning (C-RIC), is the repetitive inflation and deflation of a blood pressure cuff on the limbs for periods of weeks or months and may be an “exercise mimetic”. Our data in the VCID mouse model shows that C-RIC is cerebroprotective, increasing cerebral blood flow and collateral remodeling and improving cognition. Our central hypothesis is that C-RIC triggers a cerebroprotective phenotype by activation of peripheral limb AMPK and eNOS with an increase in circulating plasma nitrite and “endocrine NO activity” leading to increased CBF, angiogenesis, and collateral remodeling. Our sub-hypothesis is that these effects of C-RIC are age and sex independent. Our Specific aims are: Aim 1: Determine the critical role of eNOS in mediating C-RIC induced cerebroprotection and vascular remodeling upon eNOS. Aim 2: Determine the dependence of C-RIC cerebroprotection upon endothelial- specific AMPK1, an upstream regulator of eNOS. We will utilize an endothelial specific AMPKα mouse knockout (KO) model to determine whether RIC’s protection is dependent upon endothelial AMPKα1. Aim 3: Determine the role of bone marrow (BM) -derived cells in C-RIC-induced angiogenesis and collateral remodeling. eNOS in BM cells may be critical to the mechanism of C-RIC. These studies will help us to define the mechanism of C-RIC in cerebroprotection and help us translate C-RIC from the bench to the bedside in patients with VCID to reduce dementia.

到2050年，痴呆症的患病率预计将增加两倍，使其成为世界公共卫生的主要威胁。血管