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Mechanisms by which CD74 Contributes to Traumatic Brain Injury

CD74 导致创伤性脑损伤的机制

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要创伤性脑损伤 (TBI) 以及随之而来的创伤后行为和行为神经系统综合症是严重的临床问题。约500万美国人正承受着 TBI 的长期后果，而最佳的治疗方法是缺乏治疗策略。我们发现特定的成分免疫系统对 TBI 后的神经病理学有贡献。更具体地说，我们发现了 CD74，一种通过独特机制发挥作用的蛋白质明显有助于先天性或适应性免疫反应，可以被操纵以改善 TBI 后的神经退行性变和行为结果。我们的建议基于三个主要观察： 1) 我们的初步数据表明通过巨噬细胞进行全长 CD74 信号传导星形胶质细胞对 TBI 反应中的迁移抑制因子 (MIF) 结合； 2) 我们的数据表明耗尽全长 CD74 或拮抗蛋白水解 CD74 的裂解产物，II 类不变肽 (CLIP)，是抗- TBI 后的炎症和神经保护作用； 3）来自人类的最新证据临床TBI患者和实验性TBI动物模型，表现出很强的适应性免疫反应的证据，可能包括自身免疫。总的来说，这些研究很重要，因为：A）他们将评估 CD74 对先天性和适应性免疫反应的独特贡献 TBI 后； B) 他们会区分 CD74 的独特机制有助于 TBI 诱发的神经病理学和创伤后行为综合症； C) 他们将确定是否针对 CD74 的特定成分可能是 TBI 后的一种潜在治疗策略。