Neurovascular Interactions: Mechanisms, imaging, therapeutic potential

项目概要/摘要 中枢神经系统疾病时，由于血脑屏障的增加，神经血管界面发生了根本性变化 CNS实质中血浆蛋白的渗透性和流入。研究神经系统疾病通过 血管生物学、免疫学和神经科学的多学科棱镜可能对识别 新的疾病机制，发现成像工具和治疗方法， 以BBB破坏为特征的神经系统疾病。在我的实验室里， BBB破坏在CNS自身免疫、胶质细胞活化和神经变性中的功能作用。我们 确定了血液蛋白在大脑中的泄漏和神经营养因子受体信号传导作为新的分子介质 在神经血管界面调节神经胶质细胞-神经元的相互作用和大脑之间的交流 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 的神经血管界面。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联系，最终目标是为神经系统设计新的治疗方法。 疾病在本申请中，我们提出了一种多管齐下的方法来确定神经血管的作用， 神经变性、CNS修复和神经胶质细胞生物学的功能障碍，并发现新的遗传调控回路 其控制血管驱动的CNS先天免疫介导的神经毒性。我们用一种创新的实验方法 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 脑功能和这项研究的结果将适用于了解病因， 发展新的治疗几种神经系统疾病，如多发性硬化症，中风，脊髓 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.