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

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：脊柱肌肉萎缩1型（SMARD1）是由免疫球蛋白U粘合蛋白2（IGHMBP2）的功能丧失突变引起的人类运动神经元退行性疾病，一种假定的RNA/DNA旋转酶。共染色器COX先前通过位置克隆方法鉴定出小鼠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（MNM）的主要遗传修饰剂。 IGHMBP2的功能及其在运动神经元变性中的作用，该变性是SMARD1发病机理的基础。我们建议研究IGHMBP2的功能，并通过实施跨学科和机构间协作方法来揭示由IGHMBP2水平降低引起的运动神经元变性的分子缺损，这将使我们能够结合艺术生物化学和遗传研究的状态。为了实现这一目标，我们已经分离了与该解旋酶相关的IGHMBP2相互作用的蛋白质和小RNA，并且我们采用了强大的遗传方法来鉴定需要使用组织特异性转基因救援的临界细胞类型，这些临界细胞类型需要NMD基因活性。我们用至少一个修饰剂基因在遗传上操纵疾病表型严重程度的能力表明，存在分子途径，具有遗传或临床干预的潜力。因此，NMD小鼠和MNM修饰符基因提供了一个独特的机会来识别神经变性的潜在过程，并提供了干预疾病途径的可能进入点。我们的遗传研究将得到旨在表征IGHMBP2在SMARD1的细胞和小鼠模型中功能的生化研究的补充，我们将扩展来自SMARD1患者的人体组织中的研究。这些研究可能会发现RNA调节的完全新颖的途径，并将显着促进我们对运动神经元中RNA处理的理解以及RNA失调在运动神经元变性中的贡献。我们建议研究一种遗传性人类神经退行性疾病的病理学。我们的研究将阐明人类运动神经元疾病的致病机制，并促进对抗这些致命疾病的策略的设计。