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Electrophysiological phenotypes in a Drosophila model of SMA

SMA 果蝇模型的电生理表型

基本信息

批准号：
8323453
负责人：
SUBHABRATA SANYAL
金额：
$ 7.54万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8323453
关键词：
Ablation Action Potentials Address Adult Affect Alleles Attention Behavior Behavioral Biological Assay Biological Models Cells Child Childhood Defect Development Disease Drosophila genus Employee Strikes Evaluation Failure Fibroblast Growth Factor Financial compensation Functional disorder Future Gene-Modified Genetic Genetic Models Genetic Screening Growth Hereditary Disease Homologous Gene Human In Vitro Investments Laboratories Larva Lead Letters Link Maintenance Measures Mediating Modeling Motor Motor Activity Motor Neurons Muscle Muscle Weakness Muscular Atrophy Mutation Neurons Pathology Pathway interactions Performance Phenotype Physiological Physiology Preparation Property Proteins RNA Interference RNA Splicing Reagent Regulation Relative (related person)Reporting Research Role SMN protein (spinal muscular atrophy)SMN1 gene SMN2 gene Screening procedure Signal Pathway Spinal Muscular Atrophy Standardization Structure Symptoms Synapses Synaptic Receptors Synaptic Transmission Testing Therapeutic Tissues Work base efficacy testing fly genetic element genetic manipulation improved knock-down motor deficit mouse model muscle degeneration muscular system mutant neuromuscular system neuron loss neurotransmitter release novel therapeutics quantum research study response transmission process

项目摘要

DESCRIPTION (provided by applicant): Spinal muscular atrophy (SMA), one of the most widespread childhood genetic disorders in humans, is due to the loss of the telomeric SMN1 gene and partial rescue by the centromeric homolog SMN2 which is similar to SMN1 but that, due to splicing errors, makes very little functional SMN protein. Predominant symptoms include progressive failure of the neuro-muscular system, motor neuron loss, muscular weakness and atrophy. Therapeutic options are currently absent, and, therefore, their development requires aggressive investments in research to understand underlying disease mechanisms. Mouse models of SMA rely on deletion mutants that are supplemented with the human SMN2 gene, and also more recently tissue specific knock outs of SMN. Collectively, experiments using this model system have essentially supported a neuronal origin of SMA. In Drosophila, mutations in the single homolog of SMN display reduced viability, mobility defects and aberrations in the number of pre-synaptic contacts at the neuro-muscular junction (NMJ). Importantly, SMA phenotypes in flies seem to rely strongly on SMN function in muscle, and together with several reports from vertebrate models that highlight the insufficiency of a "neuron-only" model, suggest that the muscle is not a passive player in SMA pathophysiology. Indeed SMA can be viewed as a disease that arises from improper synaptic maintenance at the NMJ. A sub-optimal NMJ is likely to be defective in synaptic transmission, leading to abnormal motor behavior. However, a thorough electrophysiological evaluation of SMN mutations to understand the relative importance of reduced SMN in muscles has been lacking. Such analysis is now feasible due to the recent description of RNAi alleles that can be used to selectively knock down SMN in muscle tissue. Additionally, genetic screens have been conducted to identify genes that modify SMN dependent phenotypes in search of potential genetic elements that may be manipulated as therapy for SMA. One such candidate, the FGF pathway rescues structural defects at the synapse that arise from loss of SMN in muscles, though it is unclear whether electrophysiological defects in SMA will also be rescued by FGF. In this proposal, we address these outstanding questions by first examining electrophysiological and behavioral phenotypes that are caused by muscle specific loss of SMN in Drosophila. We next evaluate the efficacy of the FGF signaling pathway in rescuing these phenotypes. Thus, this project represents the first focused assessment of electrophysiological consequences that result from loss of SMN in the muscle tissue.

描述（由申请人提供）：脊髓性肌萎缩症（SMA）是人类最普遍的儿童遗传性疾病之一，是由于端粒SMN 1基因的丢失和着丝粒同源物SMN 2的部分拯救所致，该同源物与SMN 1相似，但由于剪接错误，产生的功能性SMN蛋白很少。主要症状包括神经肌肉系统的进行性衰竭、运动神经元丧失、肌无力和萎缩。目前缺乏治疗选择，因此，它们的发展需要积极的研究投资，以了解潜在的疾病机制。SMA的小鼠模型依赖于补充有人SMN2基因的缺失突变体，以及最近的组织特异性SMN敲除。总的来说，使用该模型系统的实验基本上支持SMA的神经元起源。在果蝇中，SMN的单一同源物中的突变显示神经肌肉接头（NMJ）处的突触前接触的数目的活力降低、移动性缺陷和畸变。重要的是，果蝇中的SMA表型似乎强烈依赖于肌肉中的SMN功能，并且与来自脊椎动物模型的几个报告一起强调了“仅神经元”模型的不足，表明肌肉在SMA病理生理学中不是被动参与者。事实上，SMA可以被视为由NMJ处的不适当的突触维持引起的疾病。次优的NMJ可能在突触传递中有缺陷，导致异常的运动行为。然而，缺乏对SMN突变的彻底电生理学评估，以了解肌肉中SMN减少的相对重要性。由于最近描述了可用于选择性敲低肌肉组织中的SMN的RNAi等位基因，这种分析现在是可行的。此外，还进行了遗传筛选，以鉴定修饰SMN依赖性表型的基因，以寻找可作为SMA治疗方法的潜在遗传元件。其中一个候选者，FGF途径挽救了由肌肉中SMN丧失引起的突触处的结构缺陷，尽管尚不清楚SMA中的电生理缺陷是否也将被FGF挽救。在这项建议中，我们解决这些悬而未决的问题，首先检查的电生理和行为表型所造成的肌肉特异性损失的SMN在果蝇。我们接下来评估FGF信号通路在挽救这些表型中的功效。因此，该项目代表了对肌肉组织中SMN丢失导致的电生理后果的第一次集中评估。