Neurovascular Interactions: Mechanisms, imaging, therapeutic potential

项目概要/摘要 由于血脑屏障增加，中枢神经系统疾病期间神经血管界面发生根本性变化 中枢神经系统实质中血浆蛋白的渗透性和流入。通过以下方式研究神经系统疾病 血管生物学、免疫学和神经科学的多学科棱镜对于识别可能至关重要 疾病的新机制、成像工具的发现和广泛的治疗方法 以血脑屏障破坏为特征的神经系统疾病。在我的实验室里，我们有了意想不到的发现 BBB 破坏在中枢神经系统自身免疫、神经胶质细胞激活和神经变性中的功能作用。我们 确定大脑中血液蛋白的渗漏和神经营养蛋白受体信号传导作为新型分子介质 在调节神经胶质-神经元串扰和大脑之间通讯的神经血管界面 和免疫系统。此外，我们开发了高分辨率双光子显微镜的新方法 体内神经血管界面。我们的目标是了解控制通信的机制 大脑、免疫和血管系统之间的研究，最终目标是设计神经系统的新疗法 疾病。在此应用中，我们提出了一种多管齐下的方法来确定神经血管的作用 神经退行性变、中枢神经系统修复和神经胶质细胞生物学功能障碍，并发现新的基因调节回路 控制血管驱动的中枢神经系统先天免疫介导的神经毒性。我们使用创新的实验 设计包括神经血管界面的体内双光子、超分辨率和电子显微镜， 电生理学、细胞生物学和信号转导、新的遗传工具和动物模型以及基因组和 蛋白质组学方法。拟议的研究将为神经血管功能障碍如何调节奠定基础 大脑功能和这项研究的结果将适用于了解病因和 开发针对多种神经系统疾病的新疗法，例如多发性硬化症、中风、脊柱 脊髓和脑损伤。

PROJECT SUMMARY/ABSTRACT The neurovascular interface fundamentally changes during CNS diseases due to increased blood-brain barrier permeability and influx of plasma proteins in the CNS parenchyma. Studying neurologic diseases through the multidisciplinary prism of vascular biology, immunology, and neuroscience could be critical for the identification of novel mechanisms of disease, discovery of imaging tools and therapeutic treatments for a wide range of neurologic diseases characterized by BBB disruption. In my laboratory we made unanticipated discoveries on the functional role of BBB disruption in CNS autoimmunity, glial cell activation, and neurodegeneration. We identified leakage of blood proteins in the brain and neurotrophin receptor signaling as novel molecular mediators at the neurovascular interface that regulate glial – neuron cross-talk and the communication between the brain and the immune system. Furthermore, we developed novel methods for high-resolution two-photon microscopy of the neurovascular interface in vivo. Our aim is to understand the mechanisms that control the communication between the brain, immune and vascular systems with the ultimate goal to design novel therapies for neurologic diseases. In this application we propose a multipronged approach to determine the role of neurovascular dysfunction in neurodegeneration, CNS repair, and glial cell biology and discover novel genetic regulatory circuits that control vascular-driven CNS innate immune mediated neurotoxicity. We use an innovative experimental design consisting of in vivo two-photon, super-resolution and electron microscopy of the neurovascular interface, electrophysiology, cell biology and signal transduction, new genetic tools and animal models, and genomic and proteomic approaches. The proposed studies will set the foundation how neurovascular dysfunction regulates brain functions and the outcomes of this research would be applicable for the understanding of the etiology and the development of new treatments for several neurologic diseases, such as multiple sclerosis, stroke, spinal cord and brain injury.