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）：脊髓性肌萎缩症（SIVIA）是一种毁灭性的遗传性神经退行性疾病，由于神经肌肉接头（NMJ）故障和最终运动神经元的丧失而导致运动功能逐渐丧失。 SMA 是由运动神经元存活 (SMN1) 丧失引起的，SMN1 是核双子复合体的一个组成部分，被认为介导 snRNP 复合体的组装和运输，从而控制关键突触蛋白的合成和传递。然而，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，从而确定可能的干预目标，以减轻哺乳动物模型或人类患者的 SMA。我们将在果蝇中使用遗传方法来识别 SMN 突变的功能修饰剂，并将在果蝇和线虫中进行研究（Artavanis-Tsakonas、van Vactor 和 Hart Laboratories）。哺乳动物细胞测定（鲁宾实验室）将扩展和证实无脊椎动物的研究，同时将使用线虫和果蝇提供的复杂遗传工具测试哺乳动物细胞中可能的功能关系和药理干预措施。每个系统都具有独特的实验优势，并且所提出的跨脊椎动物和无脊椎动物分析的整合为深入了解 SMN 生物学和病理学提供了特殊的希望，同时重要的是，它带来了确定新治疗途径的希望。