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: 10670316
• 负责人: Jerome Badaut
• 金额: $ 45.74万
• 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/10670316
• 关键词: Acceleration; Adolescent; Adult; Aging; Astrocytes; Behavior assessment; Behavioral; Binding; Blood Vessels; Blood flow; Brain; Brain Concussion; Brain Diseases; Caveolae; Caveolins; 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; Histocytochemistry; Histologic; Hospitalization; Image; Immunohistochemistry; Impaired cognition; Injections; Injury; Intelligence; Intervention; Knowledge; Lasers; Longevity; Magnetic Resonance Imaging; Modeling; Modification; Molecular; Morphology; Mus; Nature; Nerve Degeneration; Neurons; Outcome; Penetration; Perfusion; Populations at Risk; Process; Property; Proteins; Public Health; Recovery; Reporting; Research; Role; Scaffolding Protein; Signal Transduction; Signaling Molecule; Structural Protein; Structure; TBI Patients; 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; long-term sequelae; male; mild traumatic brain injury; mouse model; nervous system disorder; neuroimaging; neurovascular coupling; neurovascular unit; novel; novel therapeutics; peptidomimetics; pharmacologic; 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.

项目总结 大多数创伤性脑损伤(TBI)本质上是轻微的，但已知会导致长期后果， 包括痴呆症的出现和与年龄相关的加速衰退。高危人群是儿童 他们的大脑仍在发育中。这项提案将调查短期和长期、蜂窝 以及幼年mTBI(JmTBI)后大脑的分子变化，目的是智能地发展新的 治疗选择。小窝蛋白-1(Cav-1)是一种丰富的结构蛋白，参与小窝的形成和发育。 细胞信号在脑内皮细胞和星形胶质细胞中表达，这是 神经血管单位(NVU)。一种靶向Caveolin支架结构域的化合物的研究进展 (CSD)，一种将结构蛋白(例如claudin-5)和信号分子(例如CSD)分开的复合体。 ENOS)，为探索Cav-1在获得性神经疾病中的作用提供了工具。中风后，我们 发现Cav-1表达增加，Cav-AP治疗有利于损伤后的恢复。然而， Cav-1在其他获得性大脑中的作用是有益的还是有害的，目前尚无共识 疾病，如jmTBI。我们的jmtbi模型显示认知能力的加速丧失与 在他们的一生中血管功能下降。因此，我们将检验这一假设，即脑功能障碍 CAV-1信号转导加速钝化可预防jmTBI后的神经血管偶联 海马区和皮质的老化。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在正常(WT)和血管Cav-1缺陷的jmTBI雄性和雌性小鼠中的作用 小鼠(Cav-1-/-)和Cav-AP处理的小鼠。我们相信，经CAV-AP治疗的jmTBI小鼠将表现出 血管的恢复，而Cav-1的丢失将使NVU的预后恶化。在目标2中，我们将研究CAV- 1在反应性星形胶质细胞过程中影响jmTBI的进展。我们将直接调控Cav-1的表达 通过注射AAV-GFAP-Cav-1-shRNA和AAV-GFAP-synCav-1对正常和损伤小鼠的星形胶质细胞 量化血管恢复和行为结果。星形细胞Cav-1的增加将与 改善了NVU的特性和认知结果。在目标3中，我们将检查雄性和雌性小鼠 寿命和检查增加的Cav-1是否钝化了我们在jmTBI后观察到的大脑加速衰老。 我们将评估行为、神经成像和组织学结果。经CAV-AP治疗的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。总而言之，拟议的研究 是研究Cav-1在jmTBI中的作用的关键第一步，以及治疗干预是否可以导致 增强了NVU的稳定性和功能，从而适度加速老化。