Caveolin-1 contributes to the long-term function and structure of the neurovascular unit after juvenile concussion

Caveolin-1 有助于青少年脑震荡后神经血管单元的长期功能和结构

• 批准号: 10299440
• 负责人: Jerome Badaut
• 金额: $ 46.18万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299440
• 关键词: Adolescent; Adult; Aging; Astrocytes; Behavior assessment; Behavioral; Binding; Blood Vessels; Blood flow; Brain; Brain Concussion; Brain Diseases; Caveolae; Caveolins; Cell physiology; Cerebrovascular system; Child; Childhood; Closed head injuries; Cognition; Cognitive; Complex; Consensus; Coupling; Data; Dementia; Development; Electron Microscopy; Endothelial Cells; Exhibits; Female; Functional disorder; General Population; Genetic; Glial Fibrillary Acidic Protein; Goals; Hippocampus (Brain); Histocytochemistry; Histologic; Hospitalization; Image; Immunohistochemistry; Impaired cognition; Injections; Injury; Intelligence; Intervention; Knowledge; Lasers; Lead; Longevity; Magnetic Resonance Imaging; Modeling; Modification; Molecular; Morphology; Mus; Nature; Nerve Degeneration; Neurons; Outcome; Patients; Penetration; Perfusion; Pharmacology; Process; Property; Proteins; Public Health; Recovery; Reporting; Research; Risk; Role; Scaffolding Protein; Signal Transduction; Signaling Molecule; Structural Protein; Structure; Sum; Testing; Therapeutic Intervention; Tight Junctions; Traumatic Brain Injury; Western Blotting; abeta deposition; age related; aging brain; behavioral outcome; brain endothelial cell; caveolin 1; cognitive testing; experience; improved; improved outcome; injured; injury recovery; male; mild traumatic brain injury; mouse model; nervous system disorder; neuroimaging; neurovascular coupling; neurovascular unit; novel; novel therapeutics; post stroke; prevent; protein expression; scaffold; small hairpin RNA; synthetic peptide; tau Proteins; tool; transcytosis; two-photon

Summary Project The majority of traumatic brain injury (TBI) is mild in nature but is known to elicit long-term consequences, including emergence of dementia and accelerated age-related declines. The highest-at-risk group are children whose brains are still undergoing development. This proposal will investigate the short- and long-term, cellular and molecular changes in the brain following juvenile mTBI (jmTBI) with the goal to intelligently develop new therapeutic options. Caveolin-1 (Cav-1) is an abundant structural protein involved in caveolae formation and cell signaling which is expressed in cerebral endothelial cells and in astrocytes, key components of the neurovascular unit (NVU). Recent development of a compound to target the Caveolin Scaffolding Domain (CSD), a complex that compartmentalizes structural proteins (e.g. claudin-5) and signaling molecules (e.g. eNOS), has provided tools to explore the role of Cav-1 in acquired neurological disease. After stroke, we found increased Cav-1 expression and Cav-AP treatment was beneficial for post-injury recovery. However, consensus is lacking whether Cav-1 exhibits beneficial or deleterious actions in other acquired brain disorders, such as jmTBI. Our model of jmTBI exhibits accelerated loss of cognition associated with decreased vascular function over their lifespan. We therefore will test the hypothesis that dysfunction in neurovascular coupling after jmTBI can be prevented by modulation of Cav-1 signaling, blunting accelerated hippocampal and cortical aging. Aim 1 will demonstrate that Cav-1 is critical for maintaining NVU functionality. We examine the role of vascular Cav-1 in male & female jmTBI mice in normal (WT), vascular Cav-1 deficient mice (Cav-1-/-) and in Cav-AP treated mice. We believe that jmTBI mice treated with Cav-AP will exhibit vascular recovery, whereas the loss of Cav-1 will worsen NVU outcomes. In Aim 2 we will examine how Cav- 1 in reactive astrocyte processes influences progression of jmTBI. We will modulate Cav-1 expression directly in astrocytes by injecting AAV-GFAP-Cav-1-shRNA and AAV-GFAP-synCav-1 in control and injured mice and quantify vascular recovery and behavioral outcomes. Increased astrocytic Cav-1 will be associated with improved NVU properties and cognitive outcomes. In Aim 3 we will examine male & female mice over their lifespan and examining if increased Cav-1 blunts accelerated brain aging that we have observed after jmTBI. We will assess behavioral, neuroimaging and histological outcomes. jmTBI mice treated with Cav-AP will exhibit improved outcomes related to enhanced NVU function and integrity. In sum, the proposed research is a critical first step in examining the role of Cav-1 in jmTBI and if therapeutic intervention can lead to enhanced NVU stability and function and thereby moderate accelerated aging.

总结项目 大多数创伤性脑损伤（TBI）本质上是轻微的，但已知会引起长期后果， 包括痴呆症的出现和与年龄相关的加速衰退。风险最高的群体是儿童 他们的大脑还在发育中这项提案将调查短期和长期的，细胞 和青少年mTBI（jmTBI）后大脑中的分子变化，目的是智能地开发新的 治疗选择Caveolin-1（Cav-1）是一种丰富的结构蛋白，参与小窝的形成， 细胞信号传导，在脑内皮细胞和星形胶质细胞中表达， 神经血管单位（NVU）。靶向小窝蛋白支架结构域的化合物的最新开发 (CSD)，一种将结构蛋白（如claudin-5）和信号分子（如 eNOS），提供了探索Cav-1在获得性神经疾病中的作用的工具。中风后，我们 发现Cav-1表达增加和Cav-AP治疗有利于损伤后恢复。然而，在这方面， Cav-1在其他获得性脑损伤中是否表现出有益或有害的作用尚缺乏共识。 疾病，如jmTBI。我们的jmTBI模型表现出与以下相关的认知加速丧失： 在他们的生命周期中降低血管功能。因此，我们将测试的假设，功能障碍， jmTBI后的神经血管偶联可以通过调节Cav-1信号来阻止， 海马和皮质老化。目标1将证明Cav-1对于维持NVU功能至关重要。 我们研究了血管Cav-1在雄性和雌性jmTBI小鼠中的作用，这些小鼠在正常（WT）、血管Cav-1缺陷（WT）和正常（WT）小鼠中， 小鼠（Cav-1-/-）和Cav-AP处理的小鼠中。我们相信用Cav-AP治疗的jmTBI小鼠将表现出 血管恢复，而Cav-1的损失将恶化NVU的结果。在第二章中，我们将讨论如何在... 1在反应性星形胶质细胞过程中影响jmTBI的进展。我们将直接调节Cav-1的表达， 通过在对照和损伤小鼠中注射AAV-GFAP-Cav-1-shRNA和AAV-GFAP-synCav-1， 量化血管恢复和行为结果。星形胶质细胞Cav-1的增加将与 改善NVU特性和认知结果。在目标3中，我们将检查雄性和雌性小鼠的 寿命和检查Cav-1的增加是否会加速我们在jmTBI后观察到的大脑老化。 我们将评估行为、神经影像学和组织学结局。用Cav-AP处理的jmTBI小鼠将 表现出与增强的NVU功能和完整性相关的改善结果。总之，拟议的研究 是研究Cav-1在jmTBI中作用的关键第一步， 增强NVU稳定性和功能，从而缓和加速老化。