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Functional genomics in zebrafish to disset the pathogenesis of myofibrillar myopathies

斑马鱼功能基因组学揭示肌原纤维肌病的发病机制

基本信息

批准号：
149935633
负责人：
Professor Dr. Steffen Just
金额：
--
依托单位：
Klinik für Innere Medizin II
依托单位国家：
德国
项目类别：
Research Units
财政年份：
2009
资助国家：
德国
起止时间：
2008-12-31 至 2015-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/149935633?language=en
关键词：
Functional genomics zebrafish disset pathogenesis

项目摘要

In an attempt to develop within this consortium novel targeted treatment strategies for human myofibrillar myopathies (MFMs) our research within the first funding period aimed to elucidate the genetic basis and the mechanisms that translate known MFM mutations into the myopathic phenotype using forward and reverse genetic approaches in the zebrafish model. Loss-of-function studies of known MFM disease genes reveal that MFM genedeficient zebrafish develop heart and skeletal muscle myopathies without signs of protein aggregations, suggesting that aggregates are not the main trigger of myopathy in the zebrafish. We find that targeted depletion of putative MFM disease genes identified within this consortium (e.g. Strumpellin, KIAA1033) lead to severe myopathic phenotypes affecting both, heart and skeletal muscle, in zebrafish embryos. Additionally, we generated zebrafish that overexpress selected human MFM mutations transiently or in an inducible and stable (transgenic) manner. The transgenic lines will now allow us to evaluate MFM pathophysiology for selected human mutations.Within the second funding period we will focus on the detailed characterization of the novel MFM disease gene, Nexilin, identified by this consortium. Specific aim 1 of this project is to functionally, structurally, molecularly as well as biomechanically characterize Nexilinknockout mice which we generated during the first funding period, as well as zebrafish stably overexpressing human Nexilin mutations associated with myopathies. Specific aim 2 is to decipher the direct effects of MFM disease gene deficiency on myofiber function and structure in selected loss-of-function and transgenic zebrafish MFM disease models. Finally, specific aim 3 is to evaluate the impact/relevance of potential novel MFM disease genes recently identified within this consortium by various approaches on heart and skeletal muscle function in zebrafish.

为了试图在这个联盟内开发针对人类肌纤维肌病(MFM)的新的靶向治疗策略，我们在第一个资助期内的研究旨在阐明在斑马鱼模型中使用正向和反向遗传方法将已知的MFM突变转化为肌病表型的遗传基础和机制。对已知的MFM疾病基因的功能丧失研究表明，MFM基因缺陷的斑马鱼出现心脏和骨骼肌病而没有蛋白质聚集的迹象，这表明聚集不是斑马鱼肌病的主要触发因素。我们发现，在这个联合体中发现的可能的MFM疾病基因(例如Strumpellin，KIAA1033)的有针对性的缺失会导致斑马鱼胚胎中严重的肌病表型，影响心脏和骨骼肌。此外，我们培育的斑马鱼可以瞬时或以可诱导和稳定的(转基因)方式过表达选定的人类MFM突变。转基因株系现在将使我们能够评估选定的人类突变的MFM病理生理学。在第二个资助期内，我们将专注于该联盟发现的新的MFM病基因Nexlin的详细特征。这个项目的具体目标1是从功能上、结构上、分子上以及生物力学上表征我们在第一个资助期培育的Nexilinknock基因敲除小鼠，以及稳定过表达与肌病相关的人类Nexlin突变的斑马鱼。具体目的2是在选定的功能丧失和转基因斑马鱼MFM病模型中破译MFM病基因缺陷对肌纤维功能和结构的直接影响。最后，具体目标3是评估最近在该联盟中通过各种方法发现的潜在的MFM疾病新基因对斑马鱼心脏和骨骼肌功能的影响/相关性。