A New Approach to ALS

描述（由申请人提供）：该项目的科学目标是建立一个全面的ALS定量框架，从中可以检查起始/进展，定量地产生，预测和确定组合治疗的优先级。我们假设存在一个相互作用的病理生理谱，只有当生理学和病理学一起检查时才能看到，这组相互作用是打开我们对ALS的理解的关键，特别是它的治疗与协同作用，利用相互作用的联合治疗。我们的方法是整合来自ALS和相关生理学文献的丰富信息，结合传统的实验和临床观察，利用我们创新的“动态荟萃分析”技术，即关系建模，建立一个与ALS相关的运动神经元病理生理学的综合框架。这项提议的意义在于，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，这是传统实验单独无法实现的。研究目标包括利用文献和临床数据分析开发ALS的定量框架（目标1）；评估利鲁唑对体内电生理的影响（目的2）；在制定的框架内制定和定量评估联合治疗策略（目标3）。该提案的主要科学成果包括ALS运动神经元病理生理的综合模型，利鲁唑作用的机制洞察和潜在治疗策略的优先列表。本提案的职业发展成果包括体内神经电生理学的实践培训，临床数据分析，并将其与理论相结合，以做出临床相关的预测。

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.