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: 9752676
• 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/9752676
• 关键词: 5' -AMP-activated protein kinase; Age; Bilateral; Biological Availability; 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; Endocrine; Endothelium; Event; Exercise; Foundations; Goals; Growth Factor; Human; 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 Endothelial Growth Factors; Vascular remodeling; Work; abeta accumulation; acronyms; age effect; angiogenesis; arm; bench to bedside; blood vessel development; cerebroprotection; cognitive performance; effective therapy; improved; ischemic conditioning; mimetics; mouse model; nervous system disorder; neurovascular unit; novel; preservation; sex; 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 AMPKα 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 AMPKα1, 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.

痴呆症的患病率预计到2050年将三倍，这对世界公共卫生构成了重大威胁。血管 痴呆症占痴呆症病例的20％，血管原因又导致了30％。这些血管 首字母缩写VCID知道认知障碍和痴呆症的贡献。没有已知有效 VCID的治疗；但是，观察性研究强烈表明体育锻炼有效减少 慢性远程缺血条件（C-RIC）是 重复通货膨胀和血压袖带在四肢上的流动，数周或几个月，可能 成为“运动模仿”。我们在VCID鼠标模型中的数据表明，CRIC是脑保护的，增加了 脑血流和侧支重塑和改善认知。 我们的中心假设是，CRIC通过激活外周触发了脑保护表型 肢体AMPKα和eNOS随循环血浆亚硝酸盐和“内分泌无活性”增加 导致CBF增加，血管生成和附带重塑。我们的子假设是这些影响 c-ric是年龄和性别独立的。 我们的具体目的是： AIM 1：确定eNOS在介导C-ric诱导的脑保护和血管中的关键作用 对eNOS进行改建。 AIM 2：确定c-ric脑保护对内皮特异性AMPKα1的依赖性，上游 我们将利用内皮特异性AMPKα小鼠基因敲除（KO）模型来确定 RIC的保护是否取决于内皮AMPKα1。 AIM 3：确定骨髓（BM）衍生细胞在CRIC诱导的血管生成和侧支中的作用 重塑。 BM细胞中的eNOS可能对C-RIC机理至关重要。 这些研究将有助于我们定义CRIC在脑保护中的机制，并帮助我们翻译CRIC 从长凳到VCID患者的床边，以减少痴呆症。