Overactivation of TG-2 after traumatic brain injury

脑外伤后 TG-2 过度激活

• 批准号: 6867834
• 负责人: ANURADHA WAGHRAY
• 金额: $ 23.62万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-20 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6867834
• 关键词: Alzheimer' s disease; Lewy body; Parkinson' s disease; SDS polyacrylamide gel electrophoresis; alpha synuclein; bioinformatics; brain injury; cerebral cortex; crosslink; disease /disorder proneness /risk; enzyme activity; experimental brain lesion; gene expression; hippocampus; immunoprecipitation; laboratory rat; mass spectrometry; neuropathology; paired helical filament; polymerase chain reaction; protein glutamine gamma glutamyltransferase; protein localization; tau proteins; western blottings

DESCRIPTION (provided by applicant): Numerous studies implicate traumatic brain injury (TBI) as a risk factor for the development of age-related neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). However, a biochemical link between these disorders is missing. We propose that transglutaminase-2 (TG-2) a member of transglutaminase family could be the possible link between TBI and neurodegenerative diseases. The primary function of TG-2 is to catalyze calcium-dependent cross-linking reactions, which results in protein aggregation. Tau and a-synuclein are the principle components of neurofibrillary tangles (NFTs) and Lewy bodies (LBs), the signature pathological hallmarks of AD and PD respectively. Importantly both tau and a-synuclein are the substrates for TG-2. Recent work in our laboratory showed a sustained induction of TG-2 in the rat brain following traumatic brain injury. Our hypothesis is that TBI-induced TG-2 expression and activation may increase aggregation of tau and a-synuclein proteins and these proteins may become seeds for further homophilic deposition leading to manifestation of AD and PD. Induction of TG-2 protein and mRNA expression and its activity after TBI will be determined after1.6 mm injury magnitude at different time points for 24 months using the control cortical impact rat model. The ability of TG-2 to cross-link tau and a-synuclein proteins will be analyzed by in vitro cross-linking reaction. The antibodies against these cross-linked regions will be developed and used to determine their in vivo colocalization with TG-2 by immunoprecipitation analysis in injured rat brain tissues. In parallel the formation of NFTs and LBs will be determined in aging TBI samples using PHF and LB specific antibodies. We propose to demonstrate that TG-2 is the potential biochemical link between TBI and neurodegenerative diseases by providing evidence of sustained induction of TG-2 and its role in cross-linking of tau and a-synuclein proteins resulting in the formation of PHFs and LBs in aging rats after traumatic brain injury. The proposed study will provide critical information about the prolonged expression and activation pattern of TG-2 following TBI and will lay the necessary foundation for elucidating the potential role of TG-2 as a link between TBI and neurodegenerative diseases. This hypothesis, if proven correct, could lead to the development of potential therapeutic approaches to retard development in aging TBI patient.

描述（由申请人提供）：大量研究表明创伤性脑损伤（TBI）是与年龄相关的神经退行性疾病（例如阿尔茨海默病（AD）和帕金森病（PD））发展的危险因素。然而，这些疾病之间的生化联系缺失。我们认为转谷氨酰胺酶家族成员之一的转谷氨酰胺酶-2 (TG-2) 可能是 TBI 与神经退行性疾病之间的联系。 TG-2 的主要功能是催化钙依赖性交联反应，从而导致蛋白质聚集。 Tau 和 a-突触核蛋白是神经原纤维缠结 (NFT) 和路易体 (LB) 的主要成分，分别是 AD 和 PD 的标志性病理标志。重要的是，tau 蛋白和 a-突触核蛋白都是 TG-2 的底物。我们实验室最近的工作表明，在创伤性脑损伤后，大鼠大脑中 TG-2 持续诱导。我们的假设是，TBI 诱导的 TG-2 表达和激活可能会增加 tau 蛋白和 a-突触核蛋白的聚集，这些蛋白可能成为进一步同质沉积的种子，导致 AD 和 PD 的表现。使用对照皮质冲击大鼠模型，在24个月的不同时间点在1.6mm损伤程度后测定TBI后TG-2蛋白和mRNA表达的诱导及其活性。将通过体外交联反应分析 TG-2 交联 tau 和 a-synuclein 蛋白的能力。将开发针对这些交联区域的抗体，并通过对受损大鼠脑组织进行免疫沉淀分析来确定它们与 TG-2 的体内共定位。同时，将使用 PHF 和 LB 特异性抗体测定老化 TBI 样品中 NFT 和 LB 的形成。我们建议通过提供 TG-2 的持续诱导及其在 tau 和 a-突触核蛋白交联导致 PHF 和 LB 形成中的作用的证据来证明 TG-2 是 TBI 和神经退行性疾病之间的潜在生化联系在脑外伤后的衰老大鼠中。拟议的研究将提供有关 TBI 后 TG-2 延长表达和激活模式的关键信息，并将为阐明 TG-2 作为 TBI 和神经退行性疾病之间联系的潜在作用奠定必要的基础。如果这一假设被证明是正确的，可能会导致开发潜在的治疗方法来延缓老年 TBI 患者的发育。