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）：许多研究暗示创伤性脑损伤（TBI）是与年龄相关的神经退行性疾病（例如阿尔茨海默氏病（AD）和帕金森氏病（PD））发展的危险因素。但是，缺少这些疾病之间的生化联系。我们建议转谷氨酰胺酶-2（TG-2）跨谷氨酰胺酶家族的成员可能是TBI与神经退行性疾病之间的可能联系。 TG-2的主要功能是催化钙依赖性的交联反应，从而导致蛋白质聚集。 TAU和A-核蛋白是神经原纤维缠结（NFTS）和Lewy Bodies（LBS）的原理成分，分别是AD和PD的标志性病理标志。重要的是，tau和a-核蛋白都是TG-2的底物。我们实验室的最新工作表明，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和A-核蛋白蛋白的聚集，这些蛋白可能成为进一步同质量沉积的种子，从而导致AD和PD的表现。使用对照皮层撞击大鼠模型，将在不同时间点1.6 mm损伤幅度在不同的时间点诱导TG-2蛋白和mRNA表达及其活性。 TG-2可以通过体外交联反应来分析TG-2交叉链接TAU和A-突触核蛋白蛋白的能力。针对这些交联区域的抗体将被开发，并用于通过在受伤的大鼠脑组织中的免疫沉淀分析来确定其与TG-2的体内共定位。同时，将使用PHF和LB特异性抗体在老化的TBI样品中确定NFT和LBS的形成。我们建议证明TG-2是TBI与神经退行性疾病之间的潜在生物化学联系，通过提供持续诱导TG-2的证据及其在TAU和A-突触核蛋白蛋白交联中的作用，从而导致毒性脑损伤后PHF和LBS形成PHF和LBS。拟议的研究将提供有关TBI后TG-2的长时间表达和激活模式的关键信息，并为阐明TG-2作为TBI与神经退行性疾病之间的联系的必要作用奠定了必要的基础。该假设，如果被证明是正确的，可能会导致衰老患者的潜在治疗方法的发展。