MYOTONIC DYSTROPHY KINASE IN MYOCYTE DEVELOPMENT

肌强直性营养不良激酶在心肌细胞发育中的作用

• 批准号: 8360553
• 负责人: Erin B Harmon
• 金额: $ 24.66万
• 依托单位: SANFORD RESEARCH/USD
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360553
• 关键词: 3' Untranslated Regions; Cardiovascular system; Cell Cycle; Cells; Cellular Morphology; Data; Detection; Development; Functional disorder; Funding; Gene Expression; Genes; Goals; Grant; Hela Cells; Human; Lead; Mus; Muscle Cells; Muscle Fibers; Myoblasts; Myotonic Dystrophy; National Center for Research Resources; Patients; Phosphotransferases; Principal Investigator; Proliferating; Research; Research Infrastructure; Resources; Role; Source; Testing; Trinucleotide Repeats; United States National Institutes of Health; base; cost; myogenesis; myotonic dystrophy protein kinase; novel; overexpression; premature; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The goal of the proposed study is to identify the function of human myotonic dystrophy protein kinase (DMPK) in myocyte development. DMPK was originally identified by the detection of a CTG triplet repeat sequence located in the 3' untranslated region of the DMPK gene that is expanded in patients with myotonic dystrophy (DM1). A role for the reduced DMPK expression in the pathophysiology of DM1 cannot be determined until the function of the kinase has been clearly defined. Our preliminary data suggests DMPK may regulate myocyte development. DMPK is expressed in developing myocytes when proliferating cells transition into postmitotic cells. Overexpression studies in HeLa cells demonstrate that DMPK is sufficient to disrupt the cell cycle. The depletion of DMPK in cultured mouse myoblasts (C2C12 cells) inhibits differentiation into myotubes and alters cell morphology. We will test the novel hypothesis that DMPK has a key role in myogenesis. DMPK is required for myogenic gene expression and is sufficient to prematurely induce myogenic gene expression in myoblasts. Aim 1 will test the hypothesis that DMPK is necessary for myocyte differentiation and is sufficient to induce premature myocyte differentiation. Aim 2 will test the hypothesis that DMPK initiates exit from the cell cycle. Aim 3 will test the hypothesis that DMPK is required for the differentiation of immature myoblasts. Together, these experiments will lead to an understanding of DMPK function in muscle cell development and will lay the groundwork for treatments for DM1 based on a complete understanding of DM1 myocyte pathophysiology.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 本研究的目的是确定人强直性肌营养不良蛋白激酶（DMPK）在肌细胞发育中的功能。 DMPK 最初是通过检测位于 DMPK 基因 3' 非翻译区的 CTG 三联体重复序列来鉴定的，该序列在强直性肌营养不良 (DM1) 患者中扩增。在明确确定激酶的功能之前，无法确定 DMPK 表达减少在 DM1 病理生理学中的作用。我们的初步数据表明 DMPK 可能调节心肌细胞发育。 当增殖细胞转变为有丝分裂后细胞时，DMPK 在发育中的心肌细胞中表达。 HeLa 细胞中的过度表达研究表明 DMPK 足以破坏细胞周期。培养的小鼠成肌细胞（C2C12 细胞）中 DMPK 的消耗会抑制分化为肌管并改变细胞形态。我们将检验 DMPK 在肌生成中发挥关键作用的新假设。 DMPK 是肌源性基因表达所必需的，并且足以在成肌细胞中过早诱导肌源性基因表达。目标 1 将检验以下假设：DMPK 对于心肌细胞分化是必需的，并且足以诱导心肌细胞过早分化。目标 2 将检验 DMPK 启动细胞周期退出的假设。目标 3 将检验未成熟成肌细胞分化需要 DMPK 的假设。总之，这些实验将有助于了解 DMPK 在肌肉细胞发育中的功能，并为基于对 DM1 肌细胞病理生理学的完整了解的 DM1 治疗奠定基础。