Mechanisms by which CD74 Contributes to Traumatic Brain Injury

项目总结/摘要 创伤性脑损伤（TBI），以及随后的创伤后行为和 神经综合征是严重的临床问题。约5百万 美国人生活在TBI的慢性后果中， 缺乏治疗策略。我们发现， 免疫系统对创伤性脑损伤后的神经病理学有贡献。更具体地说， 我们发现CD 74，一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， 被操纵以改善TBI后的神经变性和行为结果。 我们的建议基于三个主要观察： 1)我们的初步数据表明全长CD 74信号通过巨噬细胞 星形胶质细胞对TBI的反应中的迁移抑制因子（MIF）结合; 2）我们的 数据表明，消耗全长CD 74或拮抗蛋白水解作用， CD 74的切割产物，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，显示出强烈的 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）它们将评估 CD 74对先天性和适应性免疫应答的不同贡献 B）它们将区分CD 74的独特机制， 导致TBI诱导的神经病理学和创伤后行为 C）他们将确定是否靶向CD 74的特定组分， 可能是TBI后潜在的治疗策略。

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.