Muscle and neuromuscular junctions in spinal muscular atrophy

脊髓性肌萎缩症中的肌肉和神经肌肉接头

• 批准号: 7652226
• 负责人: Charlotte Jane Sumner
• 金额: $ 36.93万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652226
• 关键词: Anterior; Atrophic; Biological; Cells; Chemicals; Data; Defect; Denervation; Development; Disease; Electron Microscopy; Electrophysiology (science); Enzymes; Failure; Functional disorder; Future; Gene Expression Profile; Genes; Genetic; Goals; Growth; Histone Deacetylase; Histone Deacetylase Inhibitor; Histone deacetylase inhibition; Image; Impairment; In Vitro; Individual; Infant Mortality; Inherited; Length; Measurement; Measures; Morphology; Motor; Motor Neuron Disease; Motor Neurons; Mus; Muscle; Muscle Cells; Muscle Development; Muscle Weakness; Mutation; Myoblasts; Nature; Neonatal; Nerve; Neuromuscular Junction; Pan Genus; Pathogenesis; Pathology; Pharmaceutical Preparations; Phenotype; Presynaptic Terminals; Protein Isoforms; Public Health; Research; Respiratory Diaphragm; Role; SMN protein (spinal muscular atrophy); Signal Transduction; Spinal Muscular Atrophy; Staging; Synapses; Synaptic Vesicles; Testing; Therapeutic; Time; Tissues; Work; base; effective therapy; functional improvement; improved; in vivo; insight; motor neuron function; muscular structure; myogenesis; neuromuscular transmission; neurotransmission; progenitor; public health relevance; restoration; transmission process; treatment strategy; voltage clamp

DESCRIPTION (provided by applicant): Spinal muscular atrophy (SMA) is a currently untreatable, autosomal recessive motor neuron disease that is the leading inherited cause of infant mortality. SMA is caused by deficiency of the survival motor neuron (SMN) protein. Our long term research goal is to understand the underlying pathogenesis of SMA in order to develop effective treatment strategies for this disease. Recent studies suggest that SMA begins because of intrinsic abnormalities of both muscle and motor nerve terminals; however the nature of these defects remains unknown. Histone deacetylase (HDAC) inhibitors have been shown to increase survival of SMA mice; but it is unclear how these drugs improve muscle and/or motor neuron function. In preliminary studies in SMA mice, we have shown that at a time when the mouse is profoundly weak, there is little structural denervation. However there are widespread immature and hypotrophic myofibers as well as simplified neuromuscular junctions (NMJs). Mice treated with a pan- HDAC inhibitor show a substantial extension of survival, increase in motor function, and improvement in the size and maturity of myofibers, without a change in motor neuron number. Based on these preliminary data, we hypothesize that SMN deficiency causes an arrest of muscle maturation and/or a failure of NMJ transmission that can be overcome with HDAC inhibitors, which accelerate the development of the SMA motor unit. We further hypothesize that HDAC isoform-specific drugs will have distinct biological effects on the SMA motor unit that will provide crucial insights into the therapeutic mechanism of these compounds. We will test these hypotheses by: 1) establishing whether or not a defect of muscle development contributes to SMA by studying cultured SMA muscle cells and by rescuing SMN expression specifically in muscle tissue in conditional SMA mice, 2) determining whether or not weakness in SMA is due to an impairment of neuromuscular transmission by examining the electrophysiology and morphology of the NMJs in SMA mice, and 3) characterizing the ability of HDAC inhibitors to facilitate muscle and NMJ maturation and ameliorate SMA in mice by treating SMA muscle cells and SMA mice with broadly active and HDAC-isoform specific HDAC inhibitors. PUBLIC HEALTH RELEVANCE: This work is important for public health because spinal muscular atrophy is the leading inherited cause of infant mortality and is currently untreatable. In this project, we plan to define the roles of muscle and motor neuron terminals in the pathogenesis of SMA and to explore the therapeutic mechanism of histone deacetylase inhibitors. These studies will provide important insights about what tissue and molecules are necessary to target therapeutically in SMA and will therefore guide future efforts to develop treatment for this disease.

描述(申请人提供)：脊髓性肌萎缩症(SMA)是一种目前无法治疗的常染色体隐性运动神经元病，是导致婴儿死亡的主要遗传原因。SMA是由存活运动神经元(SMN)蛋白缺乏引起的。我们的长期研究目标是了解SMA的潜在发病机制，以便制定有效的治疗策略。最近的研究表明，SMA的开始是由于肌肉和运动神经末梢的内在异常；然而，这些缺陷的性质仍然不清楚。组蛋白脱乙酰酶(HDAC)抑制剂已被证明可以提高SMA小鼠的存活率；但这些药物如何改善肌肉和/或运动神经元功能尚不清楚。在对SMA小鼠的初步研究中，我们已经表明，在小鼠极度虚弱的时候，几乎没有结构性神经丧失。然而，广泛存在未成熟和营养不良的肌纤维以及简化的神经肌肉接头(NMJ)。用PAN-HDAC抑制剂治疗的小鼠显示出显著的延长存活时间，增加运动功能，改善肌纤维的大小和成熟度，而运动神经元数量没有变化。根据这些初步数据，我们假设SMN缺乏导致肌肉成熟停滞和/或NMJ传递失败，这可以通过HDAC抑制剂来克服，从而加速SMA运动单位的发育。我们进一步假设，HDAC亚型特异性药物将对SMA运动单位产生不同的生物学效应，这将为这些化合物的治疗机制提供关键的见解。我们将通过以下方式检验这些假说：1)通过研究培养的SMA肌肉细胞和挽救有条件的SMA小鼠肌肉组织中特异的SMN表达，确定肌肉发育缺陷是否有助于SMA小鼠；2)通过检测SMA小鼠NMJ的电生理学和形态特征，确定SMA的虚弱是否是由于神经肌肉传递的损害；以及3)表征HDAC抑制剂促进小鼠肌肉和NMJ成熟及改善SMA小鼠SMA的能力，方法是用广泛活性的和HDAC亚型特异性的HDAC抑制剂处理SMA肌肉细胞和SMA小鼠。公共卫生相关性：这项工作对公共卫生很重要，因为脊髓性肌萎缩症是导致婴儿死亡的主要遗传原因，目前无法治愈。在这个项目中，我们计划确定肌肉和运动神经元终末在SMA发病机制中的作用，并探索组蛋白脱乙酰酶抑制剂的治疗机制。这些研究将为SMA的治疗靶向需要哪些组织和分子提供重要的见解，因此将指导未来开发这种疾病的治疗方法。