The role of arteriogenesis on structural and functional neurovascular recovery after cerebral stroke

动脉生成对脑卒中后结构和功能神经血管恢复的作用

• 批准号: 10043803
• 负责人: Jeanne T Paz
• 金额: $ 49.31万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10043803
• 关键词: 3-Dimensional; Address; Alteplase; American Heart Association; Animals; Area; Arteries; Behavior; Behavioral; Biological Assay; Biological Markers; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain Injuries; Brain imaging; Brain region; Cardiovascular Diseases; Cell Culture Techniques; Chronic; Clinical; Coronary; Country; Disease; Electrodes; Endothelial Cells; Endothelium; Forelimb; Funding; Generations; Goals; Image; Impairment; Implant; Individual; Infarction; Injections; Intravenous; Knowledge; Lead; Light; Link; Mediating; Mental Depression; Microscope; Microscopy; Mus; Patients; Play; Recovery; Recovery of Function; Rehabilitation therapy; Resolution; Role; Social isolation; Stroke; Structure; Testing; Therapeutic; Time; Vascular remodeling; Visualization; Walking; Work; adverse outcome; angiogenesis; arteriole; behavior test; brain health; disability; experience; imaging approach; improved; in vivo; loss of function; migration; motor deficit; mouse model; neovascularization; neurovascular; neurovascular coupling; new growth; new therapeutic target; overexpression; partial recovery; post stroke; response; sham surgery; shear stress; stroke patient; stroke recovery; stroke rehabilitation; stroke therapy; theories; tool; transcription factor

SUMMARY Cerebral stroke leads to long-term disability, yet post-stroke treatment remains primarily limited to rehabilitation. The partial functional recovery that does occur is due in part to neurovascular plasticity of the brain region adjacent to stroke damage—the peri-stroke penumbra. However, attempts to manipulate the neurovasculature post-stroke by promoting angiogenesis—sprouting of new capillary vessels—have not been successful, in part because angiogenesis can lead to tortuous, leaky vessels that do not increase blood flow. Alternatively, arteriogenesis—the generation of large-bore vessels in response to shear stress—could play an important role in post-stroke recovery and represent a novel therapeutic target. However, the lack of tools to specifically manipulate arteriogenesis has hampered efforts to test this hypothesis. We identified Dach1 as an endothelial transcription factor as a tool to specifically drive arteriogenesis. Here, we will use new mouse models that allow us to bi-directionally control Dach1 levels in endothelial cells, to determine to what extent arteriogenesis is involved in post-stroke recovery of brain functions. Specifically, we will examine the links between arteriogenesis and post-stroke recovery of the vascular network (Aim 1), neurovascular coupling (Aim 2), and behavior (Aim 3). Our long-term goal is to understand the mechanisms of adaptive post-stroke neurovascular plasticity to develop new treatments and improve brain health. Funding of this proposal will enable an unbiased study of the brain following stroke with unprecedented temporal and spatial resolution in freely behaving animals, identify the specific role of arteriogenesis in post-stroke recovery, and may unveil new therapeutic targets that enhance the therapeutic window of post-stroke rehabilitation, which is a key limiting factor in treating stroke patients.

摘要 中风会导致长期残疾，但中风后的治疗仍主要局限于 康复。部分功能恢复的发生部分是由于神经血管的可塑性 与中风损伤相邻的脑区--中风周围半暗带。然而，试图操纵 卒中后的神经血管通过促进血管生成--新的毛细血管的萌发--尚未得到 成功，部分原因是血管生成可能导致曲折的、泄漏的血管，而这些血管不会增加血流量。 或者，动脉形成--对剪应力的反应产生大口径血管--也可以发挥作用。 在卒中后恢复中起重要作用，代表了一个新的治疗靶点。然而，由于缺乏工具， 对动脉形成的具体操作阻碍了检验这一假说的努力。我们确认达奇1号是 血管内皮细胞转录因子作为特异性驱动动脉生成的工具。在这里，我们将使用新鼠标 允许我们双向控制内皮细胞中Dach1水平的模型，以确定在多大程度上 动脉生成参与了中风后脑功能的恢复。具体来说，我们将检查这些链接 在动脉形成和卒中后血管网络恢复之间(目标1)，神经血管偶联 (目标2)和行为(目标3)。 我们的长期目标是了解卒中后适应性神经血管可塑性的机制 开发新的治疗方法，改善大脑健康。为这项提案提供资金将使我们能够对 在行为自由的动物中，中风后的大脑具有前所未有的时间和空间分辨率， 确定动脉形成在卒中后恢复中的具体作用，并可能揭示新的治疗靶点 加强卒中后康复的治疗窗口是治疗卒中的关键限制因素 病人。