Genetic Modeling for SMA Therapeutic Pathways

SMA 治疗途径的基因建模

• 批准号: 8704292
• 负责人: David L. Van Vactor
• 金额: $ 125.04万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704292
• 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; Small Nuclear Ribonucleoproteins; Spinal Muscular Atrophy; Symptoms; Synapses; System; Testing; Therapeutic; Vertebrates; novel therapeutics; prevent; screening; 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，由于神经肌肉连接（NMJs）功能障碍和最终运动神经元的丧失，导致运动功能的进行性丧失。SMA是由运动神经元（SMN1）的存活丧失引起的，SMN1是核gemin复合物的一个组成部分，被认为介导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。然而，SMN相关靶基因的身份和功能以及SMN在NMJ中的确切分子作用在很大程度上仍然是一个谜。该项目的重点将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突变的功能修饰因子，并将在果蝇和秀丽隐杆线虫中研究它们（Artavanis-Tsakonas， van Vactor和Hart实验室）。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，而在哺乳动物细胞中确定的可能的功能关系和药理干预将使用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，跨脊椎动物和无脊椎动物的拟议分析的整合为深入了解SMN生物学和病理学提供了非凡的希望，同时，重要的是，它带来了确定新的治疗途径的希望。

项目成果

A screen for regulators of survival of motor neuron protein levels.

• DOI: 10.1038/nchembio.595
• 发表时间: 2011-06-19
• 期刊: NATURE CHEMICAL BIOLOGY
• 影响因子: 14.8
• 作者: Makhortova, Nina R.;Hayhurst, Monica;Cerqueira, Antonio;Sinor-Anderson, Amy D.;Zhao, Wen-Ning;Heiser, Patrick W.;Arvanites, Anthony C.;Davidow, Lance S.;Waldon, Zachary O.;Steen, Judith A.;Lam, Kelvin;Ngo, Hien D.;Rubin, Lee L.
• 通讯作者: Rubin, Lee L.

Large-Scale Production of Mature Neurons from Human Pluripotent Stem Cells in a Three-Dimensional Suspension Culture System.

• DOI: 10.1016/j.stemcr.2016.05.010
• 发表时间: 2016-06-14
• 期刊: Stem cell reports
• 影响因子: 5.9
• 作者: Rigamonti A;Repetti GG;Sun C;Price FD;Reny DC;Rapino F;Weisinger K;Benkler C;Peterson QP;Davidow LS;Hansson EM;Rubin LL
• 通讯作者: Rubin LL

A cell-autonomous defect in skeletal muscle satellite cells expressing low levels of survival of motor neuron protein.

• DOI: 10.1016/j.ydbio.2012.05.037
• 发表时间: 2012-08-15
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: Hayhurst M;Wagner AK;Cerletti M;Wagers AJ;Rubin LL
• 通讯作者: Rubin LL

In Vivo Modelling of ATP1A3 G316S-Induced Ataxia in C. elegans Using CRISPR/Cas9-Mediated Homologous Recombination Reveals Dominant Loss of Function Defects.

• DOI: 10.1371/journal.pone.0167963
• 发表时间: 2016
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sorkaç A;Alcantara IC;Hart AC
• 通讯作者: Hart AC

Studying human disease using human neurons.

• DOI: 10.1016/j.brainres.2016.03.051
• 发表时间: 2017-02-01
• 期刊: BRAIN RESEARCH
• 影响因子: 2.9
• 作者: Ahfeldt, Tim;Litterman, Nadia K.;Rubin, Lee L.
• 通讯作者: Rubin, Lee L.