Neurovascular Interactions: Mechanisms, imaging, therapeutic potential

神经血管相互作用：机制、成像、治疗潜力

• 批准号: 10477958
• 负责人: Katerina Akassoglou
• 金额: $ 141.6万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477958
• 关键词: Animal Model; Biology; Blood Proteins; Blood Vessels; Brain; CNS autoimmunity; Cellular biology; Central Nervous System Diseases; Communication; Development; Disease; Electron Microscopy; Electrophysiology (science); Epilepsy; Etiology; Experimental Designs; Extravasation; Foundations; Functional disorder; Genetic; Genomics; Goals; Image; Imaging Device; Immune; Immune system; Immunology; Laboratories; Mediating; Mediator of activation protein; Methods; Molecular; Multiple Sclerosis; Nerve Degeneration; Nerve Growth Factor Receptors; Neuroglia; Neurons; Neurosciences; Outcomes Research; Plasma Proteins; Proteomics; Receptor Signaling; Resolution; Role; Signal Transduction; Stroke; Therapeutic; Vascular System; blood-brain barrier disruption; blood-brain barrier permeabilization; design; glial activation; in vivo; innovation; multidisciplinary; nervous system disorder; neuroinflammation; neurotoxicity; neurovascular; novel; novel therapeutics; repaired; spinal cord and brain injury; tool; two photon microscopy; two-photon

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.

项目摘要/摘要 由于血脑屏障的增加，神经血管界面在中枢神经系统疾病期间的根本变化 CNS实质中血浆蛋白的渗透性和影响。通过研究神经疾病 血管生物学，免疫学和神经科学的多学科棱镜对于识别至关重要 疾病的新机制，成像工具的发现和治疗治疗 以BBB破坏为特征的神经系统疾病。在我的实验室中，我们对 BBB破坏在CNS自身免疫，神经胶质细胞激活和神经退行性中的功能作用。我们 鉴定出血液蛋白在大脑和神经营养蛋白受体信号传导中的泄漏为新的分子介体 在调节神经胶质的神经血管界面 - 神经元串扰和大脑之间的通信 和免疫系统。此外，我们开发了高分辨率两光子显微镜的新方法 体内神经血管界面的。我们的目标是了解控制沟通的机制 在大脑，免疫和血管系统之间具有最终目标的神经系统疗法的目标 疾病。在此应用中，我们提出了一种多收益的方法来确定神经血管的作用 神经退行性，中枢神经系统修复和神经胶质细胞生物学的功能障碍，并发现新的遗传调节回路 控制血管驱动的CNS先天免疫组介导的神经毒性。我们使用创新的实验 设计由体内两光子，神经血管界面的超分辨率和电子显微镜组成， 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。拟议的研究将奠定神经血管功能障碍调节的基础 大脑功能和这项研究的结果将适用于理解病因和 开发几种神经系统疾病的新疗法，例如多发性硬化症，脊柱，脊柱 绳索和脑损伤。