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ANO5 in Muscle Health and Disease

ANO5 in Muscle Health and Disease
ANO5 在肌肉健康和疾病中的作用
批准号:
10378023
负责人:
Renzhi Han
金额:
$38.36万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-04-01 至 2022-12-31

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项目成果

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中文摘要
翻译
项目摘要 ANO 5中的突变与包括肌肉萎缩症在内的几种人类疾病有关。Ano 5是一个 细胞内膜蛋白,属于anoctamin蛋白家族。这个家族中的许多蛋白质 已发现具有Ca 2+激活的磷脂扰乱活性。尽管基因上 ANO 5与肌营养不良症患者之间的联系,我们发现小鼠中ANO 5的完全KO 在上一次资助期间没有明显的肌肉病变这一点得到了其他人的独立证实。 研究人员使用不同系的完全Ano 5-KO小鼠。这些发现表明, 补偿机制,可能通过其他anoctamin蛋白,参与最大限度地减少影响, 完全缺乏Ano 5。有趣的是,表达截短的Ano 5肽的Ano 5-KO小鼠 出现肌营养不良的临床体征,伴有细胞内聚集和膜修复缺陷。 许多与人类肌营养不良症相关的ANO 5突变是过早终止突变。 这些发现提出了一个有趣的问题,即ANO 5突变如何导致人类肌肉退化。 患者:突变氨基末端Ano 5肽的表达是否通过促进 细胞内聚集体的形成和损害膜修复机制?我们继续 这项建议的研究集中在确定Ano 5的氨基末端的基本作用, 调节anoctamins蛋白质的内在脂质扰乱功能,膜修复及其对 ANO 5突变引起的肌营养不良症的发病机制。此外,我们的研究将揭示 在完全Ano 5-KO小鼠中缺乏肌营养不良表型的潜在补偿机制。 通过使用体内CRISPR基因编辑、生物化学、组织病理学和活细胞成像研究 通过动物模型,我们计划的实验将促进我们对生理和 氨基末端Ano 5肽在肌肉中的病理作用,也揭示了对肌肉的重要见解 开发用于治疗Ano 5相关肌营养不良症的新治疗策略。
英文摘要
PROJECT SUMMARY Mutations in ANO5 have been linked to several human diseases including muscular dystrophy. Ano5 is an intracellular membrane protein, belonging to the anoctamin protein family. Many of the proteins in this family have been found to possess the Ca2+-activated phospholipid scrambling activity. Despite the clear genetic linkage between ANO5 and muscular dystrophy in patients, we found that complete KO of Ano5 in mice showed no overt muscle pathology during our last funding period. This was independently confirmed by other investigators using a different line of complete Ano5-KO mice. These findings indicate that a potential compensatory mechanism, likely through other anoctamin proteins, is involved in minimizing the impact of complete Ano5 deficiency. Intriguingly, an Ano5-KO mouse expressing putatively a truncated Ano5 peptide developed clinical signs of muscular dystrophy with intracellular aggregates and defective membrane repair. Many of the ANO5 mutations associated with human muscular dystrophy are premature termination mutations. These findings raise an interesting question about how ANO5 mutations cause muscle degeneration in human patients: does the expression of mutant amino-terminal Ano5 peptide lead to muscular dystrophy by promoting the formation of intracellular aggregates and compromising membrane repair machinery? Our continuing research in this proposal is centered on determining the fundamental role of the amino-terminus of Ano5 in regulating the intrinsic lipid scrambling function of anoctamins proteins, membrane repair and its contribution to the pathogenesis of muscular dystrophy caused by ANO5 mutations. Moreover, our studies will reveal the compensatory mechanism underlying the lack of muscular dystrophy phenotype in complete Ano5-KO mice. Through the use of in vivo CRISPR gene editing, biochemical, histopathological, and living cell imaging studies with animal models, our planned experiments shall advance our understanding of the physiological and pathological roles of amino-terminal Ano5 peptides in muscle and also shed critical insights into the development of novel therapeutic strategies for the treatment of Ano5-related muscular dystrophy.
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  • 批准号:
    10268967
  • 项目类别:
  • 资助金额:
    $34.21万
  • 财政年份:
    2017
  • 负责人:
    Renzhi Han
  • 依托单位:
海外基金