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

阐明 TBI 中蛋白酶修饰 GFAP 的自身免疫反应的后果

基本信息

批准号：
8843988
负责人：
KEVIN Ka Wang WANG
金额：
$ 18.75万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2017-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8843988
关键词：
Acute Albumins Alzheimer&apos s Disease Animals Antibodies Antigen-Presenting Cells Antigens Archives Astrocytes Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity B-Lymphocytes Binding Biological Markers Blood Blood - brain barrier anatomy Blood Circulation Brain Brain Injuries CD8B1 gene Cause of Death Cell Death Cerebrospinal Fluid Chronic Chronic Phase Clinical Cohort Studies Complement Conjugated Carrier Cytotoxic T-Lymphocytes Data Development Enzyme-Linked Immunosorbent Assay Epilepsy Epitope Mapping Epitopes Event Extravasation Filtration Flow Cytometry Glial Fibrillary Acidic Protein Health Hematoxylin and Eosin Staining Method Histopathology Human Immune response Immune system Immunization Immunodominant Epitopes Immunoglobulin G Individual Infiltration Inflammatory Injection of therapeutic agent Injection product Injury Interferons Interleukin-1 Interleukin-6 Investigation Keyhole Limpet Hemocyanin Lesion Literature Lymphocyte Activation Mediating Methods Modification Multiple Sclerosis Mus Neurodegenerative Disorders Neuroglia Neuronal Injury Neurons Outcome Pathologic Patients Peptide Hydrolases Peptides Pilot Projects Population Production Proteins Public Health Rattus Recovery Reporting Risk Sampling Self Tolerance Serum Spinal cord injury Staining method Stains Stroke Structural Protein T-Lymphocyte TNF gene Technology Testing Time To autoantigen Traumatic Brain Injury axon injury base cytokine cytotoxic disability in vivo injured insight mouse model nervous system disorder novel preference response tau Proteins translational study treatment strategy

项目摘要

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.

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，据报道，美国每年约有200万起脑损伤事件。脑外伤后的头几天内会发生大量的细胞死亡，导致脑蛋白质及其分解产物大量释放到脑脊液(CSF)和循环血液等生物液体中，这是由于受损的脑血屏障促进的。我们最近进行了一项试验性的无偏研究，以检查脑外伤后患者血清中是否含有对脑损伤后的一种或多种脑特异性蛋白产生反应的自身抗体。出乎意料的是，我们发现脑外伤患者的亚急性血清中有很大一部分含有对主要星形细胞蛋白GFAP的显性自身抗体反应，这种蛋白被蛋白水解性修饰为GFAP分解产物(GFAP-BDP)。我们推测，这种酶修饰的GFAP可以破坏自身耐受性，并作为优势自身抗原，触发脑创伤后的自身免疫反应。为了验证这一假设，我们建议进行一项结合测试临床样本和进行体内小鼠自身免疫研究的翻译研究，如下所示：特定目标1将鉴定和表征脑外伤后人脑脊液和血清中的蛋白酶修饰的GFAP和伴随的自身抗体。特定目标2将检查主动GFAP-BDP抗原免疫后小鼠的系统免疫反应和脑病理后果。最后，特殊目的3将结合实验性脑损伤探讨抗GFAP-BDP自身免疫所致的小鼠病理变化。产生的数据将为脑外伤的致病机制提供有价值的见解，并可能支持旨在减轻脑外伤后公共卫生负担的治疗策略的潜在发展。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Anti-Pituitary and Anti-Hypothalamus Autoantibody Associations with Inflammation and Persistent Hypogonadotropic Hypogonadism in Men with Traumatic Brain Injury.

抗垂体和抗下丘脑自身抗体与创伤性脑损伤男性炎症和持续性低促性腺激素性腺功能减退症的关联。

DOI：
10.1089/neu.2019.6780
发表时间：
2020
期刊：
Journal of neurotrauma
影响因子：
4.2
作者：
Vijapur,SushuptaM;Yang,Zhihui;Barton,DavidJ;Vaughan,Leah;Awan,Nabil;Kumar,RajG;Oh,Byung-Mo;Berga,SarahL;Wang,KevinK;Wagner,AmyK
通讯作者：
Wagner,AmyK

Glial fibrillary acidic protein: from intermediate filament assembly and gliosis to neurobiomarker.