Mechanisms by which CD74 Contributes to Traumatic Brain Injury

CD74 导致创伤性脑损伤的机制

• 批准号: 10001758
• 负责人: M. Karen Newell Rogers
• 金额: $ 43.54万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001758
• 关键词: Address; Animal Model; Animals; Anti-inflammatory; Antigen Presentation; Antigens; Astrocytes; Attention; Autoimmunity; Behavioral; Binding; Bortezomib; Brain; Brefeldin A; Cathepsins; Cell surface; Cells; Chronic; Chronic Headaches; Cleaved cell; Clinical; Cystatins; Data; Emotional; Epilepsy; Goals; Human; Immune; Immune response; Immune system; Impaired cognition; Inflammation; Inflammatory Response; Innate Immune Response; Learning; Length; Lysosomes; Mediating; Memory; Migration Inhibitory Factor; Modeling; Molecular; Mus; Nerve Degeneration; Nervous System Trauma; Neurologic; Neurologic Dysfunctions; Outcome; Pathogenesis; Patients; Peptides; Persons; Play; Proteins; Reporting; Role; SUI1 gene; Signal Transduction; Spleen; Suggestion; Syndrome; T-Lymphocyte; Therapeutic; Time; Traumatic Brain Injury; adaptive immune response; adaptive immunity; antigen binding; base; behavioral outcome; disability; effective therapy; experimental study; fluid percussion injury; improved; improved outcome; inhibitor/antagonist; neurobehavioral; neuroinflammation; neuropathology; new therapeutic target; novel; novel therapeutics; optimal treatments; prevent; protein function; response; treatment strategy

Project Summary/ Abstract Traumatic brain injury (TBI), and the ensuing post-traumatic behavioral and neurological syndromes, are serious clinical problems. Approximately 5 million people in the U.S. are living with the chronic consequences of TBI, and optimal treatment strategies are lacking. We have discovered that specific components of the immune system contribute to neuropathology after a TBI. More specifically, we have discovered that CD74, a protein that functions via unique mechanisms that distinctly contribute to either the innate or the adaptive immune response, can be manipulated to improve neurodegeneration and behavioral outcomes after TBI. Our proposal is based on three primary observations: 1) Our preliminary data implicating full-length CD74 signaling via macrophage migration inhibitory factor (MIF)-binding in the astrocytic response to TBI; 2) Our data indicating that depleting full-length CD74 or antagonizing the proteolytic cleavage product(s) of CD74, class II invariant peptide (CLIP), are anti- inflammatory and neuroprotective after TBI; 3) Recent evidence from human clinical TBI patients and experimental TBI in animal models, showing strong evidence for an adaptive immune response, potentially including autoimmunity. Taken together, these studies are important because: A) they will assess the distinct contributions of CD74 to the innate and adaptive immune responses following TBI; B) they will distinguish between the unique mechanisms of CD74 that contribute to TBI-induced neuropathology and post-traumatic behavioral syndromes; and C) they will determine if targeting specific components of CD74 might be a potential therapeutic strategy following TBI.

项目摘要/摘要 创伤性脑损伤（TBI）以及随之而来的创伤后行为和 神经综合征是严重的临床问题。约500万 美国的人们处于TBI的长期后果和最佳状态 缺乏治疗策略。我们发现 免疫系统在TBI后有助于神经病理学。更具体地说， 我们发现CD74是一种通过独特机制起作用的蛋白质 这明显有助于先天或适应性免疫反应，可以 被操纵以改善TBI后的神经退行性和行为结果。 我们的建议基于三个主要观察结果： 1）我们的初步数据暗示通过巨噬细胞传导全长CD74信号 星形细胞对TBI的迁移抑制因子（MIF）结合； 2）我们的 数据表明耗尽全长CD74或拮抗蛋白水解 CD74，II类不变肽（夹）的切割产物是抗 TBI后的炎症和神经保护作用； 3）来自人类的最新证据 动物模型中的临床TBI患者和实验性TBI，显示出强大的 适应性免疫反应的证据，可能包括自身免疫性。 综上所述，这些研究很重要，因为：a）他们将评估 CD74对先天和适应性免疫反应的不同贡献 遵循TBI； b）他们将区分CD74的独特机制 这有助于TBI引起的神经病理学和创伤后行为 综合征； c）他们将确定是否针对CD74的特定组件 TBI之后可能是潜在的治疗策略。