Elucidate Consequences of Autoimmune Response to Protease-modified GFAP in TBI

描述（由申请人提供）：创伤性脑损伤（TBI）是全球人口死亡和残疾的主要原因，在美国每年约有200万例报道的TBI事件发生。严重的细胞死亡发生在创伤性脑损伤后的头几天，导致脑蛋白及其分解产物大量释放到脑脊液（CSF）等生物体液和循环血液中，这是由受损的脑血屏障促进的。我们最近进行了一项无偏倚的试点调查，以检查脑损伤后患者血清中是否含有对一种或多种脑特异性蛋白反应的自身抗体。出乎意料的是，我们发现相当一部分TBI患者的亚急性血清中含有对主要星形胶质细胞蛋白GFAP的显性自身抗体反应，该蛋白被蛋白水解修饰为GFAP分解产物（GFAP- bdp）。我们假设这种蛋白酶修饰的GFAP可以破坏自身耐受性，并作为主要的自身抗原触发TBI后的自身免疫反应。为了验证这一假设，我们建议进行一项结合临床样本测试和小鼠体内自身免疫研究的转化研究，具体目标1将识别和表征蛋白酶修饰的GFAP及其伴随的人类脑脊液和tbi后血清中的自身抗体。特异性目的2将检测GFAP-BDP抗原免疫后小鼠的全身免疫反应和脑病理后果。最后，Specific Aim 3将探讨抗gmap - bdp自身免疫与实验性TBI的小鼠病理变化。所产生的数据将为TBI的致病机制提供有价值的见解，并可能支持旨在减轻TBI后公共卫生负担的治疗战略的潜在发展。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a leading cause of death and disability in the human population worldwide, with approximately 2 million reported TBI events occurring in the US annually. Significant cell death occurs within the first days following TBI, resulting in a substantial release of brain proteins and their breakdown products into biofluids such as cerebrospinal fluid (CSF) and circulating blood as facilitated by the compromised brain blood barrier. We recently performed a pilot unbiased investigation to examine if post-TBI patient serum contains autoantibody reactive to one or more brain-specific proteins after TBI. Rather unexpectedly, we found that a significant portion of TBI patients' subacuet sera contains a dominant autoantibody response to a major astrocyte protein GFAP that is proteolytically modified as GFAP breakdown product (GFAP-BDP). We hypothesize that such protease modified GFAP could breakdown the self-tolerance and serve as the dominant autoantigen to trigger autoimmune response following TBI. To examine this hypothesis, we propose to conduct a translational study that combines testing clinical samples and conducting mouse autoimmune studies in vivo as the following: Specific Aim 1 will identify and characterize protease-modified GFAP and accompanied autoantibodies in human CSF and sera post-TBI. Specific Aim 2 will examine systemic immune response and brain pathological consequences in mice following active GFAP-BDP antigen immunization. Lastly, Specific Aim 3 will explore mouse pathological changes as a result of anti-GFAP-BDP autoimmunity in conjunction with experimental TBI. The data generated would provide valuable insight into the pathogenic mechanisms of TBI and likely to support potential development of treatment strategies aimed at reducing the public health burden that follows TBI.