A New Approach to ALS

描述(由申请人提供)：该项目的科学目标是开发一个全面的肌萎缩侧索硬化症的量化框架，根据该框架可以检查启动/进展情况，并对联合治疗进行量化产生、预测和优先排序。我们假设存在一个只有当生理学和病理学一起检查时才能看到的病理生理学相互作用谱，正是这一组相互作用持有关键，解锁我们对ALS的理解，特别是用协同的、相互作用-利用联合治疗来治疗ALS。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，使用我们创新的被称为关系建模的动态荟萃分析技术，开发与ALS相关的运动神经元病理生理学的全面框架。这项建议的意义在于，它将以高通量的方式产生新的、令人兴奋的ALS洞察和治疗策略，而仅靠传统的实验是不可能的。研究目标包括利用文献和临床数据分析建立肌萎缩侧索硬化症的定量框架(目标1)；评估利鲁唑对体内电生理学的影响(目标2)；以及在开发的框架内产生和定量评估联合治疗策略(目标3)。这项建议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、对利鲁唑作用的机械性洞察以及潜在治疗策略的优先列表。这项建议的职业发展成果包括在活体神经电生理学、临床数据分析方面的实践培训，以及它们与理论的结合以做出临床相关预测。

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.