Genetic Control of RNA metabolism: analysis of the SMARD1 helicase

RNA 代谢的遗传控制：SMARD1 解旋酶的分析

• 批准号: 7992374
• 负责人: ZISSIMOS MOURELATOS
• 金额: $ 34.73万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992374
• 关键词: Anabolism; Applications Grants; Binding Proteins; Biochemical; Biochemical Genetics; Biogenesis; Budgets; Cell model; Clinical; Complement; Data; Defect; Degenerative Disorder; Direct Costs; Disease; Disease Pathway; Experimental Designs; Facilities and Administrative Costs; Genes; Genetic; Goals; Guidelines; Human; Immunoglobulins; Inherited; Intervention; Investigation; Light; Metabolism; Molecular; Motor Neuron Disease; Motor Neurons; Mus; Nerve Degeneration; Neurodegenerative Disorders; Pathogenesis; Pathway interactions; Patients; Pennsylvania; Phenotype; Process; Proteins; RNA; RNA Processing; Regulation; Reporting; Research Personnel; Research Proposals; Respiratory distress; Ribosomes; Role; Severities; Small RNA; Spinal Muscular Atrophy; Text; The Jackson Laboratory; Tissues; Transfer RNA; Transgenic Organisms; Universities; base; cell type; combat; cost; design; disease phenotype; helicase; human tissue; loss of function mutation; motor neuron degeneration; mouse model; neuromuscular; novel; positional cloning; rRNA Precursor; research study

DESCRIPTION (provided by applicant): Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a human motor neuron degenerative disease caused by loss-of-function mutations of the immunoglobulin u-binding protein 2 (IGHMBP2), a putative RNA/DNA helicase. The co-investigator Cox previously identified the mouse Ighmbp2 gene as the causative gene of the mouse neuromuscular degeneration (nmd) phenotype by a positional cloning approach. We have also identified a major genetic modifier of its phenotypic expression (Mnm). The function of IGHMBP2 and its role in the motor neuron degeneration that underlies the pathogenesis of SMARD1 are unknown. We propose to investigate the function of IGHMBP2 and to uncover the molecular defect(s) responsible for motor neuron degeneration caused by reduced IGHMBP2 levels, by implementing an inter-disciplinary and inter-institutional collaborative approach that will allow us to combine state of the art biochemical and genetic investigations. Toward this goal, we have isolated IGHMBP2 interacting proteins and small RNAs that associate with this helicase and we have employed powerful genetic approaches to identify the critical cell-types that require nmd gene activity using tissue-specific transgenic rescue. Our ability to manipulate the severity of the disease phenotype genetically with at least one modifier gene suggests that a molecular pathway exists with the potential for genetic or clinical intervention. Thus, the nmd mouse and the Mnm modifier gene provide a unique opportunity to identify the underlying processes of neurodegeneration and provide possible entry points in which to intervene in the disease pathway. Our genetic studies will be complemented by biochemical studies aimed towards characterization of the function of IGHMBP2 in cellular and mouse models of SMARD1 and we will extend our studies in human tissues from SMARD1 patients. These studies will likely uncover an entirely novel pathway of RNA regulation and will advance significantly our understanding of RNA processing in motor neurons and the contribution of RNA dysregulation in motor neuron degeneration.We propose to investigate the pathobiology of an inherited, human neurodegenerative disease. Our studies will shed light on pathogenetic mechanisms of human motor neuron diseases and promote the design of strategies to combat these lethal diseases.

描述(申请人提供)：脊髓性肌萎缩症合并呼吸窘迫类型1(SMARD1)是一种人类运动神经元退行性疾病，由免疫球蛋白u结合蛋白2(IGHMBP2)功能丧失突变引起，IGHMBP2是一种假定的RNA/DNA解旋酶。该研究的合作者考克斯此前通过定位克隆的方法确定了小鼠Ighmbp2基因是小鼠神经肌肉变性(NMD)表型的致病基因。我们还确定了其表型表达的一个主要遗传修饰物(Mnm)。IGHMBP2的功能及其在SMARD1发病机制中的运动神经元退行性变中的作用尚不清楚。 我们建议通过实施跨学科和跨机构的协作方法来研究IGHMBP2的功能，并发现导致IGHMBP2水平降低导致运动神经元退化的分子缺陷(S)，这将使我们能够结合最先进的生化和遗传学研究。为了实现这一目标，我们分离了与这种解旋酶相关的IGHMBP2相互作用蛋白和小RNA，并利用强大的遗传学方法通过组织特异性转基因拯救来识别需要NMD基因活性的关键细胞类型。我们能够用至少一个修饰基因从基因上控制疾病表型的严重性，这表明存在一种具有遗传或临床干预潜力的分子途径。因此，NMD小鼠和Mnm修饰物基因提供了一个独特的机会来识别神经退化的潜在过程，并提供了可能的切入点来干预疾病途径。我们的遗传学研究将得到旨在确定IGHMBP2在SMARD1细胞和小鼠模型中的功能的生化研究的补充，我们将扩大我们在SMARD1患者的人体组织中的研究。 这些研究可能会揭示一种全新的RNA调节途径，并将极大地促进我们对运动神经元中RNA的加工以及RNA调节失调在运动神经元退变中的作用的理解。我们建议研究一种遗传性的人类神经退行性疾病的病理生物学。我们的研究将阐明人类运动神经元疾病的致病机制，并促进抗击这些致命疾病的策略的设计。