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.

预计到2050年，痴呆症的患病率将增加两倍，成为世界公共卫生的主要威胁。血管 痴呆症占痴呆症病例的20%，血管原因占另外30%。这些血管 对认知损害和痴呆的贡献已知为首字母缩写VCID。没有已知的有效 治疗VCID;然而，观察性研究强烈表明，体育锻炼是有效的， 认知能力下降和痴呆症的进展。慢性远程缺血性条件反射（C-RIC）是一种 血压袖带在肢体上的重复充气和放气达数周或数月的时间段，并且可能 做一个“运动模拟器”。我们在VCID小鼠模型中的数据显示，C-RIC具有抗肿瘤保护作用， 改善脑血流和侧支重塑，改善认知功能。 我们的中心假设是，C-RIC通过激活外周血淋巴细胞， 肢体AMPK β和eNOS与循环血浆亚硝酸盐和“内分泌NO活性”的增加 导致CBF增加、血管生成和侧支重塑。我们的子假设是这些效应 C-RIC与年龄和性别无关。 我们的具体目标是： 目的1：确定eNOS在介导C-RIC诱导的血管保护和血管内皮细胞凋亡中的重要作用。 重塑eNOS。 目的2：确定C-RIC对内皮特异性AMPK β 1的依赖性，AMPK β 1是内皮细胞的上游保护因子。 eNOS的调节剂。我们将利用内皮特异性AMPKα敲除小鼠（KO）模型来确定 RIC的保护作用是否依赖于内皮AMPKα1。 目的3：确定骨髓（BM）源性细胞在C-RIC诱导的血管生成和侧支循环中的作用 重塑BM细胞中的eNOS可能在C-RIC的机制中起关键作用。 这些研究将有助于我们明确C-RIC在脑保护中的作用机制，并帮助我们翻译C-RIC 从实验室到床旁，在VCID患者中减少痴呆症。