Targeting the Ubiquitin Proteasome System to Treat Spinal Muscular Atrophy

靶向泛素蛋白酶体系统治疗脊髓性肌萎缩症

• 批准号: 9106740
• 负责人: Barrington G Burnett
• 金额: $ 30.37万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9106740
• 关键词: Affect; Biological Assay; Cause of Death; Cells; Child; Data; Disease; Enzymes; Event; Genes; Genetic; Human; Induced Mutation; Infant; Infant Mortality; Inherited; Live Birth; Longevity; Mind; Molecular; Motor; Motor Neuron Disease; Motor Neurons; Mutation; Neuraxis; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Phosphotransferases; Protein Isoforms; Proteins; Proteolysis; RNA Splicing; RNA interference screen; Regulation; Reporter; Rodent; Role; SMN protein (spinal muscular atrophy); SMN2 gene; Spinal Muscular Atrophy; System; Testing; Therapeutic; Ubiquitin; Ubiquitination; base; disease phenotype; effective therapy; gene product; genome-wide; improved; infant death; loss of function; mouse model; multicatalytic endopeptidase complex; neuromuscular; new therapeutic target; novel; protein degradation; public health relevance; research study; restoration; small molecule; spatiotemporal; therapeutic development; ubiquitin-protein ligase

 DESCRIPTION (provided by applicant): Spinal muscular atrophy (SMA) is the most common inherited cause of death in infants and young children. SMA is caused by the deletion or mutation in the survival of motor neuron 1 (SMN1) gene, leading to a deficiency of the ubiquitously expressed SMN protein. Currently, there is no effective treatment option available for SMA. Evidence from studies in humans and rodents suggests that increasing SMN protein levels in the central nervous system is sufficient to ameliorate the disease phenotype and prolong survival. To identify protective modifiers of SMN protein levels we performed a genome-wide RNAi screen. Genes we identified in this screen will allow us to investigate genetic modifiers and molecular pathways that regulate SMN protein levels. These targets and pathways should provide novel avenues for therapeutic development for the treatment of SMA.

 描述（由申请人提供）：脊髓性肌萎缩症（SMA）是婴幼儿最常见的遗传性死亡原因。SMA是由运动神经元存活1（SMN 1）基因的缺失或突变引起的，导致普遍表达的SMN蛋白缺乏。目前，SMA尚无有效的治疗选择。来自人类和啮齿动物研究的证据表明，增加中枢神经系统中的SMN蛋白水平足以改善疾病表型并延长生存期。为了鉴定SMN蛋白水平的保护性修饰剂，我们进行了全基因组RNAi筛选。我们在此筛选中确定的基因将使我们能够研究调节SMN蛋白水平的遗传修饰剂和分子途径。这些靶点和途径应为SMA治疗的治疗开发提供新的途径。