The contributing effects of muscle, nerve and the NMJ to SMA pathology

肌肉、神经和 NMJ 对 SMA 病理的影响

• 批准号: 7802912
• 负责人: Umrao Monani
• 金额: $ 34.1万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-15 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7802912
• 关键词: Acute; Address; Affect; Anterior Horn Cells; Antigens; Atrophic; Behavioral Assay; Belief; Cells; Cessation of life; Characteristics; Childhood; Complement; Cystic Fibrosis; Defect; Development; Disease; Ensure; Failure; Frequencies; Funding; Genes; Genetic; Health; Histological Techniques; Human; Incidence; Individual; Infant; Laboratories; Limb structure; Maintenance; Molecular; Motor Neurons; Mus; Muscle; Muscle function; Muscular Atrophy; Mutation; Nerve; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neuromuscular Diseases; Neuromuscular Junction; Nucleotides; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Proteins; Reporting; Research; Role; SMN2 gene; Series; Site; Skeletal Muscle; Societies; Spinal; Spinal Cord; Spinal Muscular Atrophy; Spliced Genes; Structure; Synapses; System; Techniques; Testing; Toddler; Transgenes; Transgenic Mice; Translating; United States National Institutes of Health; base; cell type; cellular pathology; design; disease phenotype; effective therapy; human disease; mortality; mouse model; neuromuscular; neuromuscular system; neuron loss; novel; public health relevance; research study; selective expression

DESCRIPTION (provided by applicant): Proximal spinal muscular atrophy (SMA) is a common neuromuscular disorder caused by mutations in the Survival of Motor Neuron 1 (SMN1) gene and insufficient levels of its translated product, the SMN protein. SMA is the most common genetic cause of childhood mortality. Hallmarks of the disease in SMA mice and human patients include spinal motor neuron loss and skeletal muscle atrophy. Based on these characteristics it is widely believed that motor neurons are selectively vulnerable to reduced SMN and that muscle atrophy is a secondary consequence of neurodegeneration. These long-held beliefs notwithstanding, there continues to be a vigorous debate about whether motor neurons are indeed uniquely susceptible to reduced levels of SMN acting cell autonomously within them. Alternatively, neurodegeneration could be triggered by primary effects on some other cell type closely associated with motor neurons. If SMN does function within motor neurons to ensure their health and survival, it is not clear why they and not other cells are so sensitive to reduced levels of the protein. To better understand the molecular and cellular causes of SMA, mouse models that genetically mimic the human condition have been generated. In this application for funding to the NIH, we have outlined experiments described in three related aims to determine if SMA is a disease dictated exclusively by the health of the motor neurons and whether restoring normal levels of the SMN protein to this cell type is sufficient to completely ameliorate the disease phenotype. We propose to answer this question in two ways. Firstly, we will restore SMN selectively to the motor neurons of mice with SMA and ask if this results in complete phenotypic correction. Secondly, we will selectively deplete the SMN protein in the motor neurons and two associated tissues, muscle and glia, of healthy mice and ask to what extent such manipulations create neuromuscular pathology. In a second set of experiments, we will determine why insufficient SMN protein causes a selective degeneration of the neuromuscular system. To answer this question, we will look at the effects of reduced SMN on the development of the nerve-muscle synapse of SMA mice. If reduced SMN disrupts the development of this synapse and its constituent proteins which are crucial in ensuring proper nerve-muscle function, it will explain the neuromuscular pathology so characteristic of the human disease. Given the high frequency of SMA among humans, the lack of an effective treatment and the consequent burden it places on society, it is imperative that questions such as those posed here be answered in as timely a manner as possible. PUBLIC HEALTH RELEVANCE: Spinal muscular atrophy is a devastating neurodegenerative disease and the leading genetic killer of infants and toddlers. SMA is not presently treatable. Understanding why SMA results in neuromuscular failure and death is important to designing an appropriate treatment. In this proposal, we will use mouse models of the human condition to determine which cell types contribute to neuromuscular failure and why they degenerate. We believe our results will profoundly impact the design of successful therapies for SMA.

描述（由申请人提供）：脊柱肌肉萎缩（SMA）是由运动神经1（SMN1）基因存活中的突变引起的常见神经肌肉疾病，其翻译产物水平不足SMN蛋白。 SMA是儿童死亡率最常见的遗传原因。 SMA小鼠和人类患者的疾病标志包括脊柱运动神经元丧失和骨骼肌萎缩。基于这些特征，人们普遍认为，运动神经元有选择地容易降低SMN，并且肌肉萎缩是神经变性的次要结果。尽管有这些长期以来的信念，但仍有关于运动神经元是否确实完全容易受到降低的SMN作用细胞自主性自主性降低的辩论。或者，神经变性可能是由与运动神经元紧密相关的其他细胞类型的主要影响触发的。如果SMN确实在运动神经元中起作用以确保其健康和存活，则尚不清楚为什么它们而不是其他细胞对蛋白质水平降低如此敏感。为了更好地理解SMA的分子和细胞原因，已经产生了模仿人类状况的小鼠模型。在这项向NIH进行资金的申请中，我们概述了三个相关目的中描述的实验，以确定SMA是否仅由运动神经元的健康状况决定了一种疾病，以及将SMN蛋白的正常水平恢复到该细胞类型是否足以使疾病表型完全满足。我们建议通过两种方式回答这个问题。首先，我们将使用SMA选择性地将SMN选择性地恢复为小鼠的运动神经元，并询问这是否会导致完整的表型校正。其次，我们将有选择地耗尽健康小鼠运动神经元和两个相关组织的SMN蛋白，并询问这种操纵在多大程度上产生神经肌肉病理学。在第二组实验中，我们将确定为什么不足SMN蛋白会导致神经肌肉系统的选择性变性。为了回答这个问题，我们将研究SMN减少对SMA小鼠神经肌肉突触发展的影响。如果减少的SMN破坏了该突触的发展及其成分蛋白，这对于确保正确的神经肌肉功能至关重要，它将解释人类疾病的神经肌肉病理学。鉴于人类中SMA的频率很高，缺乏有效的待遇以及随之而来的社会负担，因此必须尽可能及时回答此处提出的问题。公共卫生相关性：脊柱肌肉萎缩是一种毁灭性的神经退行性疾病，是婴儿和幼儿的主要遗传杀手。 SMA目前无法治疗。了解为什么SMA导致​​神经肌肉衰竭和死亡对于设计适当的治疗很重要。在此提案中，我们将使用人类条件的小鼠模型来确定哪种细胞类型有助于神经肌肉衰竭以及为什么它们退化。我们认为，我们的结果将对SMA成功疗法的设计产生深远的影响。