The mechanism linking traumatic brain injury to amyotrophic lateral sclerosis

描述（由申请人提供）：申请人的职业目标是成为一名独立的科学家，研究神经科学和衰老领域的神经退行性疾病。一个由不同背景的导师组成的全面指导计划将确保申请人的职业发展。拟议的研究将通过加速蛋白质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）的开始和进展之间的联系。有越来越多的临床证据表明TBI与ALS有关，但这种关系中涉及的病理生理机制仍有待建立。拟议的研究将通过确定疾病发作前TBI对ALS病理开始和进展的影响来解决这一知识缺口。在fALS中，突变的SOD 1的有害作用被认为形成高分子量聚集体。TBI还增加蛋白质聚集，这是包括ALS在内的神经退行性疾病的标志。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中形成聚集体，这表明蛋白质聚集可能是一种可能的共同机制。此外，硫磺素T（ThT）抑制蛋白质聚集的作用，一种已显示结合蛋白质原纤维并减缓聚集的化合物，已显示通过减少蛋白质聚集潜在地延长寿命。基于以上概述的证据，三个具体目标解决关于创伤性损伤在ALS进展中的作用的关键问题：1）建立TBI对ALS起始和进展的影响; 2）确定TBI对ALS相关蛋白表达和聚集的影响; 3）阐明硫磺素T（ThT）是否可以减少蛋白聚集并调节ALS起始和进展。这些调查的综合结果将导致更好地了解与ALS病因有关的TBI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。拟议的研究是有意义的，因为他们将探索一种新的干预措施硫磺素T（ThT）对ALS相关蛋白表达和聚集的调节的影响。该提案的创新之处在于将TBI和ALS模型相结合，以确定它们对疾病病理学的协同作用。因此，这些研究将 对我们理解TBI在神经退行性疾病进展中的作用有重大影响，并将导致TBI和ALS治疗的改善。 公共卫生相关性：肌萎缩侧索硬化（amyotrophiclateralsclerosis，ALS）是一种进展迅速、致死性神经系统疾病，近年来发现其与创伤性脑损伤（traumaticbrainininjury，TBI）有关，但其病理生理机制尚不明确。拟议的研究将通过确定疾病发作前TBI对ALS起始和进展的影响以及对ALS相关蛋白（SOD1，TDP-43）表达和聚集的影响来解决这一差距。此外，还将研究硫磺素T（ThT）抑制蛋白质聚集的效果，ThT是一种已显示出结合蛋白质原纤维并减缓聚集的化合物。

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. PUBLIC HEALTH RELEVANCE: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, invariably fatal neurological disease has been recently linked to traumatic brain injury (TBI), however the pathophysiological mechanisms involved in this relationship remain to be established. The proposed studies will address this gap by determining the effect of TBI prior to disease onset on the initiation and progression of ALS and effects on ALS associated protein (SOD1, TDP-43) expression and aggregation. 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 will be studied.