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

项目摘要/摘要 中风会导致长期的残疾，但中风后的治疗仍然主要局限于康复。 确实发生的部分功能恢复是由于脑区神经血管的可塑性。 邻近卒中损伤--卒中周围半暗带。然而，试图操纵神经血管系统 卒中后通过促进血管生成--新的毛细血管的萌发--在一定程度上并不成功 因为血管生成可能会导致曲折、渗漏的血管，而不会增加血流量。或者， 动脉生成--在剪应力作用下产生大口径血管--可能起到重要作用 在卒中后康复方面，代表着一个新的治疗靶点。然而，缺乏工具来具体地 操纵动脉生成阻碍了检验这一假说的努力。我们鉴定了Dach1，一种内皮细胞 转录因子，作为动脉形成的特定驱动因素。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Dach1的水平，以确定动脉形成在多大程度上参与 中风后脑功能的恢复。具体地说，我们将研究动脉形成和后遗症之间的联系。 中风的血管网络恢复(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发展的机制 新的治疗方法和改善大脑健康。这项提议的资金将使对大脑的公正研究成为可能 在自由行为的动物中，以前所未有的时间和空间分辨率中风后，识别 动脉形成在卒中后恢复中的特定作用，并可能揭示新的治疗靶点，以增强 卒中后康复的治疗窗口，这是治疗卒中患者的关键限制因素。 这项多样性补充赠款将大大增强Zanib Naeem女士的研究潜力，并使 她竞争一流的生物医学博士和医学博士/博士项目。Naeem女士将参与一项 团队项目，专注于中风的神经生物学，并在体内获得小鼠行为分析方面的专业知识 电生理学和成像，以及数据分析。她还将参加后Bac股权计划 和学习(推动)课程活动，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 机会，如赠款撰写研讨会和模拟面试。

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.