Novel genetic determinants of the neuromuscular SMA phenotype

神经肌肉 SMA 表型的新遗传决定因素

基本信息

批准号：
8468220
负责人：
Umrao Monani
金额：
$ 33.78万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8468220
关键词：
Affect Animal Model Animals Backcrossings Biochemical Pathway Biology Cataloging Catalogs Cells Collection Congenic Strain Databases Defect Disease Ensure Exhibits Functional disorder Funding Future Generations Genes Genetic Genetic Determinism Genome Genomics Goals Health Homologous Gene Human Individual Lead Learning Light Link Maps Modification Molecular Molecular Target Motor Motor Neurons Mouse Strains Mus Mutant Strains Mice Mutation Natural History Nerve Degeneration Neuromuscular Diseases Outcome Palliative Care Pathology Pathway interactions Patients Phenotype Physiological Polymorphic Microsatellite Marker Process Program Development Proteins RNA Splicing Reporting Research Research Personnel Residual state Resort SMN2 gene Sequence Analysis Severity of illness Siblings Site Spinal Muscular Atrophy Testing Transgenes Transgenic Mice United States National Institutes of Health base comparative congenic design disease phenotype effective therapy genetic strain human disease interest mouse model mutant neuromuscular neuromuscular system novel pre-clinical protein function research study snRNP Biogenesis tool

项目摘要

DESCRIPTION (provided by applicant): Spinal muscular atrophy (SMA) is a common, frequently fatal, autosomal recessive disorder caused by homozygous mutations in the Survival of Motor Neuron 1 (SMN1) gene that lead to a deficiency of the SMN protein. Residual protein is expressed from SMN2, a partially functional homologue of the SMN1 gene. There is presently no cure for SMA. Currently available treatments are palliative at best. Although much has been learned about the pathology and natural history of the human disease and notwithstanding proof-of-concept studies demonstrating rescue of an SMA phenotype by restoring SMN to mouse models of the disease, the biochemical pathway(s) linking low levels of the protein to neurodegeneration remain(s) obscure. The single established function of SMN in orchestrating snRNP biogenesis has failed to shed adequate light on the motor neuron phenotype observed in SMA, prompting the search for additional functions of the protein and/or genes linking SMN paucity and disrupted snRNP biogenesis to neuromuscular disease. Increasing SMN2 copy number leads to higher levels of the SMN protein in patients and mutant mice and results in milder phenotypes. However, in rare instances the correlation between SMN2 copies and disease severity no longer holds, implying the existence of additional genetic modifiers of the SMA phenotype. Identifying such modifiers is one way to uncover new, disease-relevant functions of the SMN protein or reveal effector genes through which a disruption in snRNP biogenesis causes the SMA phenotype. In this application for funding to the NIH, we have outlined experiments in two related aims to exploit a modification of the disease phenotype in mouse models of SMA to map and identify modifying loci. In aim 1 congenic strains of SMA mice will be created to precisely define how different genetic backgrounds affect the mutant phenotype. Additionally, mutants from defined inter-strain crosses between the congenic SMA carriers will be generated and characterized by molecular, cellular and phenotypic means. In aim 2, mutants with the most distinct disease phenotypes will be used in linkage studies to map and eventually identify modifier loci. To confirm the disease modifying effects of the identified loci we will re-introduce them into SMA mice exhibiting a "typical" disease phenotype. Our studies will have two important outcomes. First, they will uncover novel, disease-relevant biochemical pathways and thus inform the underlying biology of spinal muscular atrophy. Second, they will identify genes that could serve as new molecular targets for future SMA therapies. The results of our experiments will constitute an important step toward the design of safe and effective treatments for SMA patients.

描述（由申请人提供）：脊柱肌肉萎缩（SMA）是由纯合突变引起的一种常见，致命的，常染色体隐性疾病，这是运动神经元1（SMN1）基因的生存中，导致SMN蛋白质的不足。残留蛋白来自SMN2（SMN1基因的部分功能同源物）。目前无法治愈SMA。目前可用的治疗充其量是姑息治疗。尽管已经了解了人类疾病的病理和自然史，尽管概念证明研究表明，通过恢复SMN与疾病的小鼠模型来拯救SMA表型，但将蛋白质含量低的生化途径与NeuroDegeneration联系起来仍然存在。 SMN在策划SNRNP生物发生中的单一建立功能未能使在SMA中观察到的运动神经元表型充分阐明，从而促使人们寻找蛋白质和/或链接SMN差异的其他功能，并破坏SMN的SNRNP生物发生与神经肌肉疾病。 SMN2拷贝数的增加导致患者和突变小鼠的SMN蛋白水平较高，并导致表型较轻。但是，在极少数情况下，SMN2副本与疾病严重程度之间的相关性不再存在，这意味着存在SMA表型的其他遗传修饰符。识别这种修饰符是发现SMN蛋白的新型，与疾病相关的功能或揭示效应子基因的一种方法，SNRNP生物发生的破坏会导致SMA表型。在这项向NIH进行资金的申请中，我们概述了两个相关目的的实验，以利用SMA小鼠模型中疾病表型的修改，以绘制并识别修饰基因座。在AIM 1中，将创建SMA小鼠的先天性菌株，以精确定义不同的遗传背景如何影响突变体表型。另外，将通过分子，细胞和表型手段产生和特征，从而产生和特征，从而产生和表征来自定义的晶体间交叉的突变体。在AIM 2中，将使用最鲜明的疾病表型的突变体用于链接研究，以绘制并最终识别修饰剂基因座。为了确认所鉴定基因座的疾病改变作用，我们将将它们重新引入表现出“典型”疾病表型的SMA小鼠中。我们的研究将有两个重要的结果。首先，他们将发现新型的，疾病与疾病的生化途径，从而告知脊柱肌肉萎缩的潜在生物学。其次，他们将确定可以作为未来SMA疗法的新分子靶标的基因。我们的实验结果将构成为SMA患者设计安全有效治疗的重要一步。