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Mechanisms Mediating NMJ Dennervation

NMJ 去神经支配的调节机制

基本信息

批准号：
9035940
负责人：
Carol Milligan
金额：
$ 23.25万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9035940
关键词：
Affect Age Aging Amyotrophic Lateral Sclerosis Animal Model Anterior Architecture Area Axon Blood capillaries Caregivers Caring Cell Death Clinical Clinical Trials Complement Complex Data Dendrites Denervation Development Disease Environment Event Exhibits Fiber Foundations Functional disorder Genes Goals Hand Health Human Laboratories Learning Mediating Mediator of activation protein Mitochondria Modeling Molecular Motor Motor Neurons Mus Muscle Muscle Fibers Muscle Weakness Myopathy Nature Nerve Neuraxis Neurodegenerative Disorders Neuroglia Neuromuscular Junction Neuronal Injury Neurons Organism Outcome Pathology Pathway interactions Patients Pattern Peripheral Physiology Predisposition Presynaptic Terminals Prevention Proteins RNA Research Research Personnel Resistance Role Series Signal Transduction Site Soleus Muscle Spinal Cord Staging Symptoms Synapses Testing Therapeutic Intervention Translating capillary density design differential expression effective therapy genome-wide interest mouse model mutant nerve supply neuronal cell body next generation sequencing novel preclinical study prevent ranpirnase research study response therapeutic development treatment strategy

项目摘要

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.

描述（由申请人提供）：肌萎缩性侧索硬化症（ALS; Lou Gehrig病）于140年前由Charcot博士于1869年首次描述;然而，其原因在很大程度上仍然未知，并且没有有效的长期治疗策略。我的实验室对发育过程中和ALS等疾病中介导运动神经元（MN）细胞死亡的机制有着长期的兴趣。该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以调节MN在发育中的存活，还可以调节病理条件和衰老。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中的神经肌肉接头（NMJ）。目前尚不清楚NMJ去神经支配是在该部位自主启动还是通过细胞体、非神经元细胞或甚至非MN中的病理启动。但所有的NMJ最初似乎都没有受到影响，只有那些快疲劳肌纤维。实验将具体研究肌肉主要由慢型纤维组成，其是否表达可促进NMJ神经支配的RNA和蛋白质的不同补体，而由快纤维表达的不同补体可能使MN在病理学和衰老中对NMJ去神经支配敏感。许多ALS研究集中在脊髓的病理学;然而，ALS的有效治疗策略将涉及脊髓和NMJ的靶点。本提案中的实验将针对ALS中研究不足的领域。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。