Ischemic Stroke in Cerebral Amyloid Angiopathy: Microvascular Injury and Recovery

脑淀粉样血管病中的缺血性中风：微血管损伤和恢复

• 批准号: 10675490
• 负责人: Olivia Marlowe Colbert
• 金额: $ 4.77万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675490
• 关键词: Affect; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Animals; Architecture; Autopsy; Basal Ganglia; Bioenergetics; Blood - brain barrier anatomy; Blood Vessels; Blood brain barrier dysfunction; Brain; Brain Injuries; Brain region; Bromodeoxyuridine; Cell Separation; Cells; Cerebral Amyloid Angiopathy; Cerebrovascular Disorders; Cerebrovascular system; Clinical; Coagulation Process; Communication; Complex; Cues; Dementia; Deposition; Diagnosis; Differentiation Antigens; Dyes; Extravasation; Functional disorder; Future; Gene Expression; Genus Hippocampus; Health; Hippocampus; Hospitals; Hour; Human; Immunohistochemistry; Impaired cognition; Infarction; Inflammasome; Inflammatory; Inflammatory Response; Interruption; Ischemia; Ischemic Stroke; Learning; Measures; Mediating; Medical; Medicine; Mitochondria; Monitor; Motor; Mus; Neurologic; Neuronal Dysfunction; Neurons; Neuropathogenesis; Outcome; Pathway interactions; Patients; Permeability; Proliferating; Proteins; Recovery; Rehabilitation therapy; Research; Risk Factors; Sampling; Severities; Signal Transduction; Sodium Fluorescein; Stains; Stroke; Therapeutic; Tight Junctions; Tissues; Transgenic Organisms; Vascular Diseases; Western Blotting; abeta accumulation; age related; behavior test; blood-brain barrier disruption; brain tissue; burden of illness; cerebral microvasculature; cerebrovascular; chemokine; clinical practice; clinically relevant; cognitive function; endothelial dysfunction; experimental study; gene complementation; insight; intercellular communication; memory process; mitochondrial dysfunction; mitochondrial metabolism; mouse model; negative affect; nerve stem cell; nervous system disorder; neurogenesis; neurological rehabilitation; neuron development; neuropathology; normal aging; post stroke; protein expression; stem cells; stroke outcome; stroke recovery; stroke survivor; targeted treatment; trafficking; translational medicine; vascular injury

Project Summary Recovery after ischemic stroke is one of the most critical rehabilitative medical problems in medicine. While current treatments are effective in removing clots, most patients do not present to hospitals before serious tissue damage occurs in the brain, with as many as two-thirds of stroke survivors requiring neurorehabilitation. Furthermore, post-stroke outcomes have been poorly studied in patients with cerebral amyloid angiopathy (CAA). CAA is a form of cerebrovascular disease and is characterized by substantial beta-amyloid (Aβ) accumulation within cerebral vasculature, including the blood-brain barrier (BBB). This condition exceeds amyloid deposits associated with normal aging and may contribute to age-related neurological decline. Additionally, Aβ accumulation in CAA is a risk factor for ischemic infarcts and degradation of vessel wall architecture. The integrity of vessel wall architecture is crucial for post-stroke tissue recovery since many proliferative neural progenitor cells (NPC) are close to and communicating with cerebral vasculature (BBB). This pool of proliferative NPCs that can become depleted by stroke can be mutually affected by Aβ accumulation, leading to delayed recovery of both motor and cognitive functions. We aim to understand the mechanism behind delayed post-stroke recovery because of both conditions so that targeted therapies can be proposed in the future. To study this, we will employ a transgenic 5xFAD mouse model that recapitulates Aβ accumulation in the brain to analyze CAA and cerebrovascular ischemia. The central hypothesis of this study is that Aβ accumulation in cerebral vasculature exacerbates ischemic stroke outcomes and delays post-stroke recovery by inducing BBB dysfunction and aberrant neurogenesis of NPCs. Experiments will focus on neurogenesis post-stroke, as well as microvascular function and the bioenergetic mechanisms that induce it. While there is no effective strategy to treat tissue damage following ischemic stroke and/or treat Aβ accumulation in the brain, this project focuses on the mechanism of CAA-related stroke in order to develop therapeutic strategies in the future. Defining neuropathogenesis of both CAA and ischemic stroke incidents is of significant relevance in translational medicine and clinical practice because most patients diagnosed with Alzheimer’s Disease (AD) also present with CAA; therefore, most of the disease burden due to CAA can be clinically relevant to treatments that also affect AD.

项目摘要 缺血性中风后的恢复是最关键的康复医学问题之一 药品。虽然目前的治疗方法可有效去除衣服，但大多数患者不参加医院 在严重的组织损伤发生在大脑中，多达三分之二的中风存活 需要神经居住。此外，中风后结局在患者中的研究很差 脑淀粉样血管病（CAA）。 CAA是脑血管疾病的一种形式，其特征是 大脑脉管系统内的大量β-淀粉样蛋白（Aβ）积累，包括血脑屏障 （BBB）。这种情况超过与正常衰老相关的淀粉样蛋白沉积物，可能有助于与年龄有关 神经系统衰落。另外，CAA中的Aβ积累是缺血性疾病和降解的危险因素 船墙建筑。容器壁建筑的完整性对于冲程后组织恢复至关重要，因为 许多增殖的神经祖细胞（NPC）都接近并与脑脉管系统（BBB）通信。 可以通过Aβ的积累互助影响的这种可以通过中风加深的增殖NPC池， 导致电动机和认知功能的恢复延迟。我们旨在了解背后的机制 由于这两种情况，因此中风后恢复延迟，因此可以在 未来。 为了研究这一点，我们将采用一个转基因5xFAD小鼠模型，该模型概括了大脑中的Aβ 分析CAA和脑血管缺血。这项研究的中心假设是Aβ在 大脑血管造成BBB，势力恢复后恢复势力降低了缺血性中风结果和延误 NPC的功能障碍和异常神经发生。实验也将重点放在震动后神经发生上 作为微血管功能及其影响它的生物能机制。虽然没有有效的策略可以 治疗缺血性中风和/或治疗大脑中Aβ积累后的组织损伤，该项目聚焦 关于与CAA相关的中风的机制，以便将来制定理论策略。定义 CAA和缺血性卒中事件的神经病发生在转化医学中均具有显着相关性 和临床实践，因为大多数被诊断为阿尔茨海默氏病（AD）的患者也出现 caa;因此，大多数由于CAA引起的疾病燃烧可能与也影响的治疗有关 广告。

项目成果

Pericyte infection by HIV-1: a fatal attraction.

• DOI: 10.1186/s12977-022-00614-3
• 发表时间: 2022-12-07
• 期刊: Retrovirology
• 影响因子: 3.3