Evaluating the interaction of the immune system and inflammation on the progression of blast-mediated neurodegeneration.

评估免疫系统和炎症对急变介导的神经变性进展的相互作用。

• 批准号: 10574502
• 负责人: Matthew M. Harper
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574502
• 关键词: Accounting; Acute; Adaptive Immune System; Adoptive Transfer; Affect; American; Animals; Astrocytes; Autoantibodies; B-Lymphocytes; Blast Injuries; Blindness; Brain; Cause of Death; Cell Death; Cell Separation; Cells; Cellular Immunity; Central Nervous System; Cessation of life; Chronic; Clinical; Complement; Complement Activation; Complement Membrane Attack Complex; Data; Defect; Detection; Devices; Drug Utilization; Exposure to; Eye; Gene Expression; Generations; Goals; Health; Humoral Immunities; Immune; Immune response; Immune system; Individual; Infiltration; Inflammation; Injury; Knowledge; Mediating; Microglia; Mus; Nerve Degeneration; Neuronal Dysfunction; Neurons; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Pharmaceutical Preparations; Process; Quality of life; Retina; Role; Signal Transduction; Splenocyte; Structure; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Tissues; Translating; Transplantation; Traumatic Brain Injury; Veterans; Vision; Wild Type Mouse; adoptive B cell transfer; blast exposure; clinically relevant; experience; experimental study; immune activation; improved; improved outcome; inhibitor; microorganism; neuroinflammation; neuron loss; novel therapeutic intervention; prevent; receptor; response; service member

Traumatic brain injury (TBI) is a leading cause of death, accounting for ~30% of all injury deaths in America, with over 2 million Americans acquiring some form of TBI. Approximately 20% of current service members have experienced some form of TBI. Many recent injuries have come in the form of exposures to blast from improvised explosive devices. Blast TBI triggers an activation of the immune system, generation of auto- antibodies, as well as infiltration of circulating immune cells into the central nervous system (CNS). These mechanisms occur in the brain as well as the retina. However, the individual role of cellular and humoral immunity causing neuron loss has not been thoroughly dissected. This proposal will define the role of auto- antibodies and circulating immune cells on the progression of blast-mediated visual loss in order to identify mechanisms that are amenable to therapy. The overall goal of this study is to determine which components of the immune response are necessary and sufficient to cause neuronal dysfunction and loss after blast-mediated TBI. Our central hypothesis is that blast-mediated traumatic brain injury activates cellular and humoral immune responses that lead to increased chronic neurodegeneration after TBI. Understanding how immune cells, autoantibodies, and complement protein affect eyes exposed to blast represents a critical knowledge gap. Our study should reveal novel therapeutic approaches utilizing drugs already approved for clinical use that can be immediately translated to benefit Veteran’s health.

创伤性脑损伤（TBI）是死亡的主要原因，占美国所有损伤死亡的约30%， 超过两百万美国人患有某种形式的创伤性脑损伤约20%的现役军人 经历过某种形式的TBI。最近的许多伤害都是以暴露于爆炸的形式出现的， 简易爆炸装置冲击性创伤性脑损伤会激活免疫系统，产生自体免疫系统。 抗体，以及循环免疫细胞浸润到中枢神经系统（CNS）。这些 机制发生在大脑以及视网膜。然而，细胞和体液的个体作用 导致神经元损失的免疫力尚未被彻底剖析。该提案将界定汽车的作用， 抗体和循环免疫细胞对胚细胞介导的视力丧失进展的影响， 可以接受治疗的机制。 本研究的总体目标是确定免疫应答的哪些组分是必需的， 足以在胚细胞介导的TBI后引起神经元功能障碍和损失。 我们的中心假设是爆炸介导的创伤性脑损伤激活了细胞和体液免疫， 这些反应导致TBI后慢性神经变性增加。 了解免疫细胞、自身抗体和补体蛋白如何影响暴露于爆炸的眼睛 这是一个关键的知识缺口。我们的研究应该揭示利用药物的新治疗方法 已经批准用于临床使用，可以立即转化为有益于退伍军人的健康。