Mechanisms by which CD74 Contributes to Traumatic Brain Injury

项目摘要/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。大约500万 美国人正在忍受脑损伤的慢性后果，最好的 缺乏治疗策略。我们发现，特定的组件 免疫系统在脑外伤后的神经病理中起作用。更确切地说， 我们已经发现CD74，一种通过独特机制发挥功能的蛋白质 对先天免疫反应或获得性免疫反应有明显贡献的物质，可以 被操纵以改善脑外伤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结果： 1)我们的初步数据涉及通过巨噬细胞传递全长CD74信号 脑外伤后星形胶质细胞反应中迁移抑制因子(MIF)的结合；2)OUR 数据表明，耗尽全长CD74或拮抗蛋白水解物 CD74二类不变肽(CLIP)的切割产物(S)具有抗肿瘤活性。 颅脑损伤后的炎症和神经保护；3)来自人类的最新证据 临床脑外伤患者和动物模型实验脑损伤显示出很强的相关性 适应性免疫反应的证据，可能包括自身免疫。 综上所述，这些研究很重要，因为：a)它们将评估 CD74在先天和获得性免疫反应中的不同作用 在TBI之后；B)他们将区分CD74的独特机制 与脑创伤后的神经病理和创伤后行为有关 症状；以及C)他们将确定是否针对CD74的特定组件 可能是脑外伤后的一种潜在的治疗策略。

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.