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: 7537177
• 负责人: ZISSIMOS MOURELATOS
• 金额: $ 35.5万
• 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 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7537177
• 关键词: Address; Alanine-Specific tRNA; Alleles; Arts; Binding Proteins; Biochemical; Biochemical Genetics; Biogenesis; Candidate Disease Gene; Cells; Cessation of life; Clinical; Code; Complement; Complex; Defect; Degenerative Disorder; Disease; Disease Pathway; Genes; Genetic; Genetic Transcription; Goals; Hela Cells; Human; Hybrids; Immunoglobulins; Individual; Inherited; Intervention; Investigation; Light; Metabolism; Modification; Molecular; Motor; Motor Neuron Disease; Motor Neurons; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathway interactions; Patients; Phenotype; Process; Protein Biosynthesis; Proteins; RNA; RNA Helicase; RNA Processing; RNA Splicing; Regulation; Research; Research Personnel; Respiratory distress; Ribosomal RNA; Ribosomes; Role; Severities; Small Nucleolar RNA; Small Nucleolar Ribonucleoproteins; Small RNA; Spinal Muscular Atrophy; Tissues; Transfer RNA; Transgenic Mice; Transgenic Organisms; Tyrosine-Specific tRNA; U3 small nucleolar RNA; cell type; chromatin remodeling; combat; design; disease phenotype; general transcription factor IIIC1 alpha subunit; helicase; human tissue; loss of function; loss of function mutation; motor neuron degeneration; mouse model; mutant; neuromuscular; novel; overexpression; positional cloning; promoter; protein function; research study; transcription factor

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（由申请方提供）：1型脊髓性肌萎缩伴呼吸窘迫（SMARD 1）是一种由免疫球蛋白u结合蛋白2（IGHMBP 2）（一种推定的RNA/DNA解旋酶）功能缺失突变引起的人类运动神经元退行性疾病。合作研究者考克斯先前通过定位克隆方法鉴定了小鼠Ighmbp 2基因为小鼠神经肌肉变性（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。IGHMBP 2的功能及其在运动神经元变性中的作用是SMARD 1发病机制的基础，目前尚不清楚。 我们建议研究IGHMBP 2的功能，并通过实施跨学科和跨机构的合作方法，使我们能够联合收割机结合最先进的生化和遗传研究，以揭示由IGHMBP 2水平降低引起的运动神经元变性的分子缺陷。为了实现这一目标，我们已经分离出IGHMBP 2相互作用的蛋白质和小RNA，与这种解旋酶，我们已经采用强大的遗传方法来确定关键的细胞类型，需要nmd基因的活性，使用组织特异性转基因救援。我们的能力，操纵疾病的严重程度表型遗传与至少一个修饰基因表明，分子途径存在的遗传或临床干预的潜力。因此，nmd小鼠和Mnm修饰基因提供了一个独特的机会，以确定神经变性的潜在过程，并提供可能的切入点，在其中干预疾病途径。我们的遗传研究将通过生物化学研究来补充，旨在表征SMARD 1细胞和小鼠模型中IGHMBP 2的功能，我们将扩展我们在SMARD 1患者人体组织中的研究。 这些研究可能会发现一个全新的RNA调控途径，并将大大推进我们对运动神经元中RNA加工的理解，以及运动神经元degeneration.We建议调查遗传性人类神经退行性疾病的病理生物学。我们的研究将揭示人类运动神经元疾病的发病机制，并促进对抗这些致命疾病的策略的设计。