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

项目摘要/摘要 脑卒中导致长期残疾，但卒中后治疗仍主要限于康复。 部分功能恢复的发生部分是由于神经血管可塑性的大脑区域 邻近中风损伤-中风周围半影区。然而，试图操纵神经血管系统 通过促进血管新生--新毛细血管的发芽--来治疗中风后的疾病， 因为血管生成会导致扭曲、渗漏的血管，而这些血管不会增加血流量。可选择地， 动脉生成--即在剪切应力作用下生成大口径血管--可能起着重要作用 并代表了一种新治疗靶点。然而，缺乏具体的工具， 操纵动脉生成阻碍了检验这一假设的努力。我们鉴定了Dach 1， 转录因子，作为动脉生成的特定驱动因素。在这里，我们将使用新的小鼠模型，使我们能够 双向控制内皮细胞中的Dach 1水平，以确定动脉生成在多大程度上参与 中风后大脑功能的恢复。具体来说，我们将研究动脉形成和后动脉形成之间的联系。 中风后血管网络的恢复（目标1）、神经血管耦合（目标2）和行为（目标3）。 我们的长期目标是了解适应性卒中后神经血管可塑性的机制， 新的治疗方法和改善大脑健康。这项提案的资助将使对大脑的无偏见研究成为可能。 在自由行为的动物中，以前所未有的时间和空间分辨率识别中风后， 动脉生成在中风后恢复中的特定作用，并可能揭示新的治疗靶点， 脑卒中后康复的治疗窗口，这是治疗脑卒中患者的关键限制因素。 这项多样性补充补助金将大大提高扎尼布·纳伊姆女士的研究潜力， 她的顶级生物医学科学博士和MD/博士课程的竞争力。纳伊姆女士将参与一个 团队项目，重点是中风的神经生物学，并获得在小鼠行为测定，在体内的专业知识 电生理学和成像以及数据分析。她还将参加后Bac公平计划 在PROPEL课程活动中，PI（Jeanne Paz）担任导师。通过 推进计划，Naeem女士将参加生物医学研讨会，并获得职业发展 机会，如赠款写作讲习班和模拟面试。

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.