The mechanism linking traumatic brain injury to amyotrophic lateral sclerosis

描述(申请人提供)：应聘者的职业目标是成为一名在神经科学和衰老领域研究神经退行性疾病的独立科学家。一个全面的导师计划，由不同背景的导师组成的团队将确保申请者的职业发展。建议的研究将通过加速蛋白表达和聚集的机制来解决创伤性脑损伤(TBI)和肌萎缩侧索硬化症(ALS)的启动和进展之间的联系。越来越多的临床证据表明脑外伤与肌萎缩侧索硬化症有关，但这种关系的病理生理学机制仍有待确定。拟议的研究将通过确定疾病发作前的脑外伤对ALS病理的启动和进展的影响来解决这一知识缺口。在FALS中，突变的SOD1的有害影响被认为形成了高分子量聚集体。脑损伤还会增加蛋白质聚集，这是包括ALS在内的神经退行性疾病的一个标志。有趣的是，另一种蛋白质，反式激活反应或TAR DNA结合蛋白43(TDP-43)，在ALS和TBI中都形成聚集，这表明蛋白质聚集可能是一种可能的共同机制。此外，硫黄素T(THT)对蛋白质聚集的抑制作用已被证明是一种结合蛋白质纤维和缓慢聚集的化合物，已被证明可能通过减少蛋白质聚集来延长寿命。基于上述证据，有三个具体的目的旨在解决关于创伤在ALS进展中的作用的关键问题：1)建立脑损伤对ALS启动和进展的影响；2)确定脑损伤对ALS相关蛋白表达和聚集的影响；3)阐明硫代黄素T(THT)是否可以减少蛋白聚集并调节ALS的启动和进展。这些研究的综合结果将有助于更好地理解脑外伤与肌萎缩侧索硬化症的发病机制。这些研究将提供分子生物学、动物模型、免疫组织化学、行为分析和组织形态计量学方面的培训。所提出的研究具有重要意义，因为它们将探索一种新的干预措施硫代黄素T(THT)对ALS相关蛋白表达和聚集的调节作用。这一建议的创新之处在于将TBI和ALS模型结合起来，以确定它们在疾病病理学上的协同作用。因此，这些研究将 对我们理解脑损伤在神经退行性疾病进展中的作用有重大影响，并将导致改善脑损伤和肌萎缩侧索硬化的治疗。

DESCRIPTION (provided by applicant): The applicant's career goal is to become an independent scientist studying neurodegenerative disease in the fields of neuroscience and aging. A comprehensive mentoring plan with a team of mentors of diverse backgrounds will ensure the applicants career development. The proposed studies will address the link between traumatic brain injury (TBI) and amyotrophic lateral sclerosis (ALS) initiation and progression through the mechanism of accelerated protein expression and aggregation. There is increased clinical evidence linking TBI to ALS but the pathophysiological mechanisms involved in this relationship remain to be established. The proposed studies will address this gap in knowledge by determining the effect of TBI prior to disease onset on initiation and progression of ALS pathology. In fALS, the detrimental effects of the mutated SOD1 are thought to form high molecular weight aggregates. TBI also increases protein aggregation, a hallmark of neurodegenerative disease including ALS. Interestingly, another protein, transactivation response or TAR DNA Binding Protein 43 (TDP-43), forms aggregates in both ALS and TBI which suggests that protein aggregation could be a possible common mechanism. In addition, the effect of the inhibition of protein aggregation by thioflavin T (ThT), a compound that has been shown to bind protein fibrils and slow aggregation has been shown to extend lifespan potentially through the reduced protein aggregation. Based on the evidence outlined above, three specific aims address critical questions regarding the role of traumatic injury in the progression of ALS: 1) establish the effect of TBI on initiation and progression of ALS; 2) determine the impact of TBI on ALS associated protein expression and aggregation; 3) elucidate whether thioflavin T (ThT) can reduce protein aggregation and modulate ALS initiation and progression. The combined results of these investigations will result in a better understanding of the mechanism relating TBI to ALS etiology. These studies will provide training in molecular biology, animal models, immunohistochemistry, behavioral analysis and histomorphometry. The proposed studies are significant because they will explore the effects of a novel intervention thioflavin T (ThT), on the modulation of ALS associated protein expression and aggregation. The innovation of this proposal is the combination of TBI and ALS models in order to determine their collaborative effect on disease pathology. As a result, these studies will have a significant impact on our understanding of the role of TBI on the progression of neurodegenerative disease and will lead to improved treatments for TBI and ALS.