Mechanisms Mediating NMJ Dennervation

 描述(申请人提供)：肌萎缩侧索硬化症(ALS；Lou Gehrig病)于140年前由Charcot博士于1869年首次描述；然而，其病因在很大程度上仍不清楚，也没有有效的长期治疗策略。我的实验室对调节运动神经元(MN)细胞在发育过程中死亡的机制以及ALS等疾病有长期的兴趣。这项拟议的项目建立在多年研究的基础上，其结果使我们假设肌肉不仅可能在发育过程中调节MN的存活，而且在病理条件和衰老过程中也可能调节MN的存活。在许多神经退行性疾病中，最初的损伤似乎发生在突触，即ALS中的神经肌肉连接(NMJ)。目前尚不清楚NMJ失神经是在该部位自主启动的，还是在细胞体、非神经元细胞甚至非MN中由病理引起的。但所有的NMJ最初似乎并没有受到影响，只有那些快速疲劳的肌肉纤维上的NMJ受到影响。这些实验将专门研究以慢型纤维为主的肌肉是否表达了可能促进NMJ神经支配的RNA和蛋白质的独特补充，而快速纤维表达的独特补充可能使NMJ在病理和衰老过程中易受NMJ神经支配的影响。许多ALS研究都集中在脊髓的病理学上；然而，ALS的有效治疗策略将涉及脊髓和NMJ的靶点。这项提案中的实验将针对ALS中一个调查不足的地区。我们将开始确定肌肉是否是ALS中轴突/突触丢失的关键介质，并可能为治疗开发提供基础。

 DESCRIPTION (provided by applicant): Amyotrophic Lateral Sclerosis (ALS; Lou Gehrig's Disease) was first described by Dr. Charcot 140 years ago in 1869; however, its causes remain largely unknown and effective, long-term treatment strategies are not available. My laboratory has a long-term interest in mechanisms mediating motoneuron (MN) cell death during development and in diseases such as ALS. The proposed project builds on years of research whose results have led us to hypothesize that muscle may regulate MN survival not only in development, but also in pathological conditions and aging. In many neurodegenerative diseases initial damage appears to occur at synapses, the neuromuscular junctions (NMJs) in ALS. It is not known whether NMJ denervation is initiated autonomously at that site or by pathology in the cell body, in non-neuronal cells or even in non-MNs. But all NMJs do not appear to be affected initially, only those on fast fatigable muscle fibers. The experiments will specifically investigate if muscle composed predominantly slow type fibers express a distinct complement of RNA and proteins that may promote NMJ innervation whereas the distinct complement expressed by fast fibers may make MNs susceptible to NMJ denervation in pathology and aging. Much ALS research has focused on pathology in the spinal cord; however, effective treatment strategies for ALS will involve targets in both spinal cord and at the NMJ. The experiments in this proposal will target an under-investigated area in ALS. We will begin to determine if muscle is a key mediator axon/synapse loss in ALS and possibly provide foundation for therapeutic development.