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: 10406125
• 负责人: Jeanne T Paz
• 金额: $ 9.03万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406125
• 关键词: 3-Dimensional; Address; Alteplase; American Heart Association; Animals; Arteries; Behavior; Behavioral; Behavioral Assay; 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; Data Analyses; Disease; Doctor of Philosophy; Educational Curriculum; Educational workshop; Electrodes; Electrophysiology (science); Endothelial Cells; Endothelium; Forelimb; Funding; Generations; Goals; Grant; Image; Impairment; Implant; Individual; Infarction; Injections; Interview; Intravenous; Knowledge; Lead; Learning; Light; Link; Mediating; Mental Depression; Mentors; Microscope; Microscopy; Mus; Neurobiology; Play; Recovery; Recovery of Function; Rehabilitation therapy; Research; Resolution; Role; Science; Social isolation; Stroke; Structure; Testing; Therapeutic; Time; Vascular remodeling; Visualization; Walking; Work; Writing; adverse outcome; angiogenesis; behavior test; brain health; career development; 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; parent grant; partial recovery; post stroke; programs; response; sham surgery; shear stress; stroke patient; stroke recovery; stroke rehabilitation; stroke therapy; theories; tool; transcription factor

PROJECT SUMMARY/ABSTRACT 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, an endothelial transcription factor, as a specific driver of 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. This diversity supplement grant will significantly enhance the research potential of Ms. Zanib Naeem, and make her competitive for top-tier biomedical science PhD and MD/PhD programs. Ms. Naeem will be involved in a team project that focuses on the neurobiology of stroke, and gain expertise in mouse behavioral assays, in vivo electrophysiology and imaging, and data analysis. She will also participate in the Post-Bac Program for Equity and Learning (PROPEL) curriculum activities, on which the PI (Jeanne Paz) serves as a mentor. Through the Propel program, Ms. Naeem will both participate in biomedical seminars and have access to career development opportunities, such as grant writing workshops and mock interviews.

项目摘要/摘要 大脑中风会导致长期残疾，但中风后治疗仍主要仅限于康复。 确实发生的部分功能恢复部分归因于大脑区域的神经血管可塑性 邻近中风损伤 - 冲刺半月。但是，试图操纵神经血管系统 通过促进血管生成（新毛细血管视频的刺），并不成功，部分原因是 因为血管生成会导致曲折，漏水不会增加血液流动。或者， 动脉生成 - 响应剪切应力的大孔血管的产生 - 应该起重要作用 在中风后恢复中，代表了一种新型的治疗靶标。但是，缺乏专门的工具 操纵动脉生成已经阻碍了检验该假设的努力。我们确定了Dach1，一种内皮 转录因子，是动脉生成的特定驱动因素。在这里，我们将使用新的鼠标模型，使我们能够 双向控制内皮细胞中的DACH1水平，以确定小动脉生成在多大程度上涉及 中风后脑功能的恢复。具体而言，我们将检查动脉生成与后的动脉生成之间的联系 血管网络（AIM 1），神经血管耦合（AIM 2）和行为（AIM 3）的中风恢复。 我们的长期目标是了解自适应后中风后神经血管可塑性的机制 新疗法并改善大脑健康。该提案的资金将使大脑无偏研究 在以自由表现的动物中前所未有的临时和空间分辨率进行中风后，确定 动脉生成在冲程后恢复中的特定作用，并可能揭示出增强新的治疗靶标 中风后康复的治疗窗口，这是治疗中风患者的关键限制因素。 这种多样性补充赠款将大大增强Zanib Naeem女士的研究潜力，并使 她在顶级生物医学博士学位和MD/PHD计划中有竞争力。 Naeem女士将参与 团队项目的重点是中风的神经生物学，并获得鼠标行为测定方面的专业知识，体内 电生理学和成像以及数据分析。她还将参加BAC股权计划 和学习（Propel）课程活动，PI（Jeanne Paz）在其上是一种心理。通过 推进计划，Naeem女士都将参加生物医学半手，并可以进入职业发展 机会，例如授予写作研讨会和模拟访谈。