Genetic Modeling for SMA Therapeutic Pathways

SMA 治疗途径的基因建模

• 批准号: 8291245
• 负责人: David L. Van Vactor
• 金额: $ 131.95万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8291245
• 关键词: Attenuated; Biological Assay; Biological Models; Biology; Caenorhabditis elegans; Childhood; Complex; Disease; Drosophila genus; Gene Targeting; Genetic; Genetic Models; Health; Human; Inherited; Intervention; Invertebrates; Laboratories; Lead; Mammalian Cell; Mediating; Modeling; Molecular; Motor; Motor Neuron Disease; Motor Neurons; Mutation; Neurodegenerative Disorders; Neuromuscular Junction; Nuclear; Pathology; Pathway interactions; Patients; Proteins; Role; SMN1 gene; Screening procedure; Small Nuclear Ribonucleoproteins; Spinal Muscular Atrophy; Symptoms; Synapses; System; Testing; Therapeutic; Vertebrates; novel therapeutics; prevent; tool

DESCRIPTION (provided by applicant): Spinal Muscular Atrophy (SIVIA) is a devastating inherited neurodegenerative disease causing progressive loss of motor functions due to malfunction of neuromuscular junctions (NMJs) and eventual loss of motor neurons. SMA is caused by loss of Survival of Motor Neuron (SMN1), a component of the nuclear gemin complex which is thought to mediate assembly and transport of snRNP complexes and thus control the synthesis and delivery of key synaptic proteins. However, the identity and function of relevant SMN target genes and the precise molecular role of SMN at the NMJ remain largely a mystery. The proposed project focus will be to use simple genetic model systems to dissect the mechanism(s) by which SMN controls synaptic form and function, and thus identify likely targets for interventions to attenuate SMA in mammalian models or human patients. We will be using genetic approaches in Drosophila to identify functional modifiers of SMN mutations and will study them in both Drosophila as well as C.elegans (Artavanis-Tsakonas, van Vactor and Hart Laboratories). Mammalian cell assays (Rubin laboratory) will extend and corroborate the studies in invertebrates while possible functional relationships and pharmacological interventions identified in mammalian cells will be tested using the sophisticated genetic tools that C elegans and Drosophila offer. Each system has unique experimental advantages and the integration of the proposed analysis across vertebrates and invertebrates offers exceptional promise for an in depth understanding of SMN biology and pathology while, importantly, it carries the promise of identifying novel therapeutic avenues.

描述（由申请人提供）：脊柱肌肉萎缩（SIVIA）是一种毁灭性的遗传神经退行性疾病，导致由于神经肌肉连接（NMJS）故障导致运动功能的逐渐丧失，最终导致运动神经元丧失。 SMA是由运动神经元（SMN1）的存活率丧失引起的，这是核双子座复合物的一个成分，被认为可以介导SNRNP复合物的组装和运输，从而控制关键突触蛋白的合成和递送。但是，相关SMN靶基因的身份和功能以及SMN在NMJ中的精确分子作用在很大程度上仍然是一个谜。拟议的项目重点是使用简单的遗传模型系统来剖析SMN控制突触形式和功能的机制，从而确定可能针对干预措施减轻SMA的靶标的SMA或人类患者。我们将使用果蝇中的遗传方法来鉴定SMN突变的功能修饰符，并将它们在果蝇和C.Elegans（Artavanis-Tsakonas，van Vactor和Hart Laboratories）中进行研究。哺乳动物细胞分析（Rubin实验室）将扩展并证实无脊椎动物的研究，而在哺乳动物细胞中发现的功能关系和药理学干预措施将使用C秀丽隐杆线虫和果蝇提供的复杂遗传工具进行测试。每个系统都有独特的实验优势，并且跨脊椎动物和无脊椎动物的拟议分析的整合为对SMN生物学和病理的深入了解提供了非凡的希望，而重要的是，它具有识别新型治疗途径的希望。