Mechanistic role of vascular dysfunction in TBI-mediated cognitive dysfunction

血管功能障碍在 TBI 介导的认知功能障碍中的机制作用

• 批准号: 10391335
• 负责人: JONATHAN LIFSHITZ
• 金额: --
• 依托单位: PHOENIX VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391335
• 关键词: Acute; Aerobic Exercise; Affect; Afghanistan; Aging; Alzheimer' s Disease; Animals; Attenuated; Blood Vessels; Brain; Brain Injuries; Brain-Derived Neurotrophic Factor; Carbon Dioxide; Cardiac; Cardiovascular system; Cerebrovascular Disorders; Cerebrum; Chronic; Coronary artery; Data; Dementia; Development; Diffuse; Disease; Echocardiography; Endothelium; Exposure to; Genetic Predisposition to Disease; Goals; Histopathology; Homeostasis; Hypertension; Impaired cognition; Impairment; Inbred SHR Rats; Injury; Iraq; Knowledge; Lead; Link; Magnetic Resonance Imaging; Measures; Mediating; Modeling; Molecular; Morbidity - disease rate; Neurons; Organ; Outcome Measure; Pathologic; Pathway interactions; Perfusion; Physiological; Play; Rattus; Regulation; Reporting; Rest; Role; Soldier; Sprague-Dawley Rats; Structure; Testing; Traumatic Brain Injury; Vascular Dementia; Vascular Diseases; Vascular blood supply; Veterans; Work; Youth; base; cardiovascular effects; cardiovascular risk factor; cerebral artery; cerebrovascular; chronic traumatic encephalopathy; cognitive development; cognitive function; disorder risk; early onset; exercise training; fluid percussion injury; hypertensive; improved; in vivo; insight; mild traumatic brain injury; military veteran; mortality; neurovascular; neurovascular coupling; normotensive; novel; object recognition; pressure; prevent; rehabilitation strategy; response; service member; sham surgery; stressor; synergism

Abstract Mild traumatic brain injury (mTBI) is a major cause of mortality and morbidity especially among service- members and veterans. mTBI is linked to long-term development of dementia conditions such as Alzheimer's disease and related disorders, but the exact pathophysiologic mechanisms remain poorly-defined. Vascular disease and cardiovascular risk factors are strongly linked with dementia. We propose to test the hypothesis that long-term mTBI-induced cognitive dysfunction is due to, at least in part, persistent cerebrovascular dysfunction. We will also test the hypothesis that early onset mTBI and later development of hypertension will have synergistic effects on cerebrovascular and cognitive dysfunction compared to hypertension or mTBI alone. In Aim 1, we will measure the temporal changes (subacute and chronic) in cerebrovascular and cognitive function in a rat model of mTBI while establishing the mechanistic role of cerebrovascular dysfunction in mTBI-induce cognitive impairment. Following midline fluid percussion injury or sham surgery in Sprague-Dawley rats, we will measure subacute (8 weeks) and chronic (12 months) cerebrovascular function (in-vivo by brain contrast MRI and ex-vivo by measuring cerebral artery vasoreactivity) and cognitive function and establish their relationship. We will also determine if early (starting at 2 weeks post-injury) or late (starting at 10 months post-injury) aerobic exercise training will improve cerebrovascular function leading to improvement in cognitive function. We will identify molecular mechanisms by which cerebrovascular function modulates cognitive function in mTBI by investigating the role of endothelial function in the regulation of brain-derived neurotrophic factor. In Aim 2, we will probe the interaction between early onset mTBI and later development of hypertension in chronic cerebrovascular and cognitive dysfunction. Here we will use rats genetically prone to develop hypertension (spontaneously hypertensive rats) to determine the effects of early onset mTBI in modulating chronic cerebrovascular and cognitive function. We will also have an exploratory aim to look at effects of mTBI in Sprague-Dawley and hypertensive rats on cardiac structure and function and coronary artery function. The proposal could provide critical and novel insights on the mechanisms underlying vascular dysfunction in TBI and their role in the development of cognitive dysfunction.

抽象的 轻度创伤性脑损伤（MTBI）是死亡率和发病率的主要原因，尤其是在服务中 - 成员和退伍军人。 MTBI与痴呆症的长期发展有关，例如阿尔茨海默氏症 疾病和相关疾病，但确切的病理生理机制仍然很差。血管 疾病和心血管危险因素与痴呆症密切相关。我们建议检验以下假设 长期MTBI诱导的认知功能障碍至少部分是由于持续性脑血管功能障碍所致。 我们还将检验以下假设：早期发作MTBI和后来的高血压发展将具有协同作用 与仅高血压或MTBI相比，对脑血管和认知功能障碍的影响。在AIM 1中，我们将 在大鼠模型中测量脑血管和认知功能中的时间变化（亚急性和慢性） MTBI的同时确定脑血管功能障碍在MTBI诱导认知中的机械作用 损害。在Sprague-Dawley大鼠中的中线流体​​打击乐损伤或假手术后，我们将测量 亚急性（8周）和慢性（12个月）的脑血管功能（脑对比度MRI和EX-VIVO的体体 通过测量脑动脉血管反应性）和认知功能并建立其关系。我们也会 确定早期（在伤害后2周开始）还是晚（在伤害后10个月开始）有氧运动 训练将改善脑血管功能，从而改善认知功能。我们将确定 脑血管功能通过研究通过研究MTBI调节认知功能的分子机制 内皮功能在调节脑源性神经营养因子中的作用。在AIM 2中，我们将调查 MTBI早期发作与后来在慢性脑血管中的高血压发展之间的相互作用 认知功能障碍。在这里，我们将使用易于遗传的大鼠发展高血压（自发 高血压大鼠）确定MTBI早期发作对调节慢性脑血管和 认知功能。我们还将有一个探索性的目的，以研究MTBI在Sprague-Dawley和 高血压大鼠心脏结构和功能以及冠状动脉功能。该提议可以提供 对TBI血管功能障碍的机制的批判性和新颖见解及其在 认知功能障碍的发展。