A New Approach to ALS

描述（由申请人提供）：本项目的科学目标是开发一个全面的ALS定量框架，从中可以检查起始/进展，并定量生成、预测和优先考虑联合治疗。我们假设存在一个病理生理学的相互作用谱，只有当生理学和病理学一起检查时才能看到，正是这组相互作用是解开我们对ALS的理解的关键，特别是它的治疗与协同，相互作用开发组合治疗。我们的方法是整合来自ALS和相关生理文献的丰富信息，结合传统的实验和临床观察，使用我们创新的“动态荟萃分析”技术（称为关系建模）开发ALS相关运动神经元病理生理学的综合框架。该提案的重要性在于，它将以高通量的方式产生新的和令人兴奋的ALS见解和治疗策略，而仅凭传统实验是不可能的。研究目的包括使用文献和临床数据分析开发ALS的定量框架（目的1）;评估利鲁唑对体内电生理学的影响（目的2）;以及在开发的框架内生成和定量评估联合治疗策略（目的3）。该提案的主要科学成果包括ALS运动神经元病理生理学的综合模型，对利鲁唑作用的机理见解和潜在治疗策略的优先列表。该提案的职业发展成果包括在体内神经电生理学，临床数据分析，以及它们与理论的整合，使临床相关的预测动手培训。 公共卫生相关性：在这个项目中，我们使用了一种创新的方法，我们的“动态元分析”的形式被称为关系建模，它集成了理论，实验和临床数据分析，以创建一个定量的ALS框架，从该框架中可以做出关于病理进展的临床相关预测。使用这个开发的框架，我们将生成和定量评估新的ALS治疗，无论是单独还是组合。该提案的科学成果是ALS治疗策略的优先列表，职业发展成果是传统神经电生理学和临床神经退行性评估的实践培训。

DESCRIPTION (provided by applicant): The scientific objective of this project is to develop a comprehensive quantitative framework of ALS from which initiation/progression can be examined and combination treatments be quantitatively generated, predicted, and prioritized. We hypothesize that there exists a pathophysiological spectrum of interactions that can only be viewed when physiology and pathology are examined together, and it is this set of interactions that holds the key to unlocking both our understanding of ALS and especially its treatment with synergistic, interaction-exploiting combination treatments. Our approach is to integrate the wealth of information derived from the ALS and related physiological literature, in conjunction with traditional experimental and clinical observations, to develop a comprehensive framework of ALS-relevant motoneuron pathophysiology using our innovative "dynamic meta-analysis" technique, referred to as relational modeling. The significance of this proposal is that it will generate new and exciting ALS insight and treatment strategies in a high-throughput manner not possible with traditional experimentation alone. The research aims consist of developing a quantitative framework of ALS using both the literature and clinical data analysis (aim 1); assess the effects of riluzole on in vivo electrophysiology (aim 2); and generating and quantitatively assessing combination treatment strategies within the developed framework (aim 3). The primary scientific outcomes of this proposal include a comprehensive model of ALS motoneuron pathophysiology, mechanistic insight into the actions of riluzole and a prioritized list of potential therapeutic strategies. The career development outcomes of this proposal include hands-on training in in vivo neuroelectrophysiology, clinical data analysis, and their integration with theory to make clinically relevant predictions. PUBLIC HEALTH RELEVANCE: In this project, we use an innovative method, our form of "dynamic meta-analysis" referred to as relational modeling that integrates theory, experimental, and clinical data analysis to create a quantitative framework of ALS from which clinically relevant predictions can be made regarding pathology progression. Using this developed framework, we will generate and quantitatively assess novel ALS treatments, both singly and in combination. The scientific outcome of this proposal is a prioritized list of ALS therapeutic strategies, with the career development outcomes being hands-on training in traditional neuroelectrophysiology and clinical neurodegenerative assessment.