Cellular and molecular mechanisms of brain repair by glial scar formation following stroke

中风后神经胶质疤痕形成脑修复的细胞和分子机制

• 批准号: 9335461
• 负责人: Kristian Paul Doyle
• 金额: $ 33.02万
• 依托单位: UNIVERSITY OF ARIZONA
• 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 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335461
• 关键词: Ablation; Acute; Address; Adult; Affect; Albumins; Amyloid beta-Protein; Animal Model; Antibodies; Area; Astrocytes; B-Lymphocytes; Biochemical; Biological Assay; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; Cholesterol; Chronic; Cicatrix; Cognitive deficits; Complement; Confocal Microscopy; Data; Defect; Dementia; Development; Diffusion; Electron Microscopy; Environment; Extravasation; Failure; Flow Cytometry; Genetic; Goals; Homocysteine; Human; Immunoassay; Immunohistochemistry; Impaired cognition; Impairment; Infiltration; Inflammation; Inflammatory Response; Injectable; Injury; Interleukin-6; Lesion; Modeling; Molecular; Monitor; Mus; Nerve Degeneration; Neuropil; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Plasma Cells; Process; Recovery; Regulation; Resolution; Rest; Rheumatoid Arthritis; Role; Route; STAT3 gene; Signal Pathway; Signal Transduction; Site; Spinal cord injury; Stroke; Subcategory; Survivors; Testing; Tight Junctions; Time; Transferrin B; Transgenic Mice; Vascular Dementia; Work; aged; analog; astrogliosis; behavioral study; brain repair; brain tissue; cytokine; foot; healing; improved; innovation; mouse model; neurotoxic; novel strategies; post stroke; prevent; repaired; response; seal; stroke recovery

PROJECT DESCRIPTION This project addresses patients' recovery from stroke and the development of post-stroke dementia, a sub- category of vascular dementia that affects approximately one-third of stroke sufferers. Following stroke, the blood brain barrier (BBB) is breached in the area of the lesion. As part of a cellular repair response, reactive astrocytes join together via an unknown mechanism to form a physical barrier to seal off the damaged area and protect the surviving neuropil. Astrogliosis and the formation of the glial scar is a critical component of the healing response to stroke. However, there have been no studies on the possibility that failure of the glial scar to perfectly seal the area of injury, which we recently demonstrated is also a site of chronic inflammatory responses, contributes to cognitive decline in patients that develop post-stroke dementia. This limitation has been due, in part, to the lack of an effective animal model of delayed cognitive dysfunction following stroke. However, we recently developed an innovative new mouse model of delayed cognitive dysfunction following stroke that models hallmarks of post-stroke dementia. Using this model, we now have substantial evidence that failure of the glial scar to segregate chronically leaky blood vessels within the lesion, as well as chronic inflammatory responses occurring in the lesion, is one cause of post-stroke dementia. Therefore the goals of this project are to determine for the first time precisely how (and how effectively) the glial scar seals the area of injury following stroke, by identifying the cellular and molecular mechanisms involved, and then to manipulate these mechanisms to enhance repair by the glial scar. These goals will be achieved by using our new mouse model of delayed cognitive dysfunction following stroke in conjunction with confocal and electron microscopy, immunohistochemistry, biochemical assays, flow cytometry, multiplex immunoassays, and behavioral studies, in adult and aged wildtype and transgenic mice. At the end of these studies we will have revealed how well the glial scar seals lesions following stroke in both adult and aged mice, interrogated a key pathway involved in glial scar regulation for which there is little data, and pharmacologically manipulated this pathway to improve the barrier function of the glial scar, and thereby protect against the development of post-stroke dementia.

项目描述 该项目致力于解决中风患者的康复和中风后痴呆症的发展问题，这是一种亚 血管性痴呆症，影响大约三分之一的中风患者。中风后， 病变区域的血脑屏障（BBB）被破坏。作为细胞修复反应的一部分，反应性 星形胶质细胞通过一种未知的机制结合在一起，形成物理屏障来封闭受损区域 并保护幸存的神经纤维。星形胶质细胞增生和神经胶质疤痕的形成是神经胶质细胞增生的重要组成部分 对中风的治愈反应。然而，目前还没有研究表明神经胶质疤痕失效的可能性 完美密封受伤区域，我们最近证明该区域也是慢性炎症部位 反应，导致中风后痴呆患者的认知能力下降。这个限制有 部分原因是缺乏有效的中风后迟发性认知功能障碍的动物模型。 然而，我们最近开发了一种创新的迟发性认知功能障碍小鼠模型 模拟中风后痴呆症特征的中风。使用这个模型，我们现在有大量证据表明 神经胶质疤痕未能隔离病变内长期渗漏的血管，以及慢性 病变中发生的炎症反应是中风后痴呆的原因之一。因此，目标是 该项目将首次准确确定神经胶质疤痕如何（以及如何有效）密封区域 中风后的损伤，通过识别所涉及的细胞和分子机制，然后操纵 这些机制可以增强神经胶质疤痕的修复。这些目标将通过使用我们的新鼠标来实现 结合共聚焦和电子显微镜的中风后迟发性认知功能障碍模型， 免疫组织化学、生化测定、流式细胞术、多重免疫测定和行为研究， 在成年和老年野生型和转基因小鼠中。在这些研究结束时，我们将揭示 神经胶质疤痕封闭了成年和老年小鼠中风后的病变，询问了参与的关键途径 胶质疤痕调节的数据很少，并且通过药理学操纵该途径来改善 神经胶质疤痕的屏障功能，从而防止中风后痴呆的发展。