Genetic regulation of muscle fiber diversity

肌纤维多样性的遗传调控

• 批准号: 7105151
• 负责人: Richard Matthew Cripps
• 金额: $ 28.17万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105151
• 关键词: Drosophilidae; actins; arthropod genetics; biological signal transduction; cell differentiation; developmental genetics; expression cloning; genetic enhancer element; genetic regulation; genetically modified animals; intermolecular interaction; mesoderm; morphometry; muscle proteins; myoblasts; myogenesis; nucleic acid sequence; protein isoforms; protein localization; protein structure function; site directed mutagenesis; striated muscles; thorax; transcription factor

DESCRIPTION (provided by applicant): The long-term objectives of this application are to understand how individual muscles assume their unique characteristics in the body, and to identify the factors which direct myoblasts towards these unique fates. All muscle cells in the body have characteristics which broadly classify them as fast or slow fibers, yet we still have a lot to learn in terms of how fiber identity is initially determined. Here, we shall use the model animal Drosophila, where the muscles of the adult thorax assume two distinct phenotypes: the fibrillar muscles which power flight; and the tubular muscles which are required for walking and jumping. Our research so far has identified the myogenic factor myocyte enhancer factor-2 (MEF2) as an important regulator of the patterning of these muscles, and in this application we shall define in detail how MEF2 functions in adult muscle development, and identify genes through which MEF2 works to control fiber patterning. Our current work has also identified a number of enhancer elements which show activity which is restricted either to the fibrillar or tubular muscles. We posit that regulators of these enhancers are critical determinants of specific muscle identities, therefore we shall identify the transcriptional regulators acting upon these enhancer and define their role in muscle development and the generation of muscle fiber diversity. These studies will define important regulatory mechanisms used to diversify the muscle lineage in animals, and given the strong evolutionary conservation in developmental mechanisms, our results will have broad relevance to the formation of muscles in higher animals, including vertebrates. We hope that the findings of our basic research will ultimately lead to new mechanisms and paradigms to comprehend how mammalian muscles form and how muscle development and function goes awry in the diseased state. Relevance to public health: This research will tell us how genes work together to make muscles in the body. Since the genes that make muscles in flies are strikingly similar to those that function in higher animals including humans, our findings will help us to understand how human muscles are formed and how specific muscles in the body function in the way that they do. We anticipate that the results of our research will allow other to better understand how muscles form, and how muscles might be disrupted under disease conditions.

描述（由申请人提供）：本申请的长期目标是了解单个肌肉如何在体内采用其独特的特征，并确定将肌细胞指向这些独特命运的因素。人体中的所有肌肉细胞都具有将它们的特征大致分类为快速或缓慢的纤维，但是我们仍然有很多关于最初确定纤维身份的知识。在这里，我们将使用模型的动物果蝇，成年胸部的肌肉采用两种不同的表型：动力飞行的原纤维肌肉；以及步行和跳跃所需的管状肌肉。到目前为止，我们的研究已经确定了肌生成因子肌细胞增强子2（MEF2）是这些肌肉模式的重要调节剂，在此应用中，我们将详细定义MEF2在成人肌肉发育中的功能，并确定MEF2通过该基因来控制纤维绘制的基因。我们目前的工作还确定了许多增强子元素，这些元素显示出限制于原纤维或管状肌肉的活性。我们认为，这些增强剂的调节剂是特定肌肉身份的关键决定因素，因此，我们将确定作用于这些增强剂的转录调节器，并确定其在肌肉发育中的作用和肌肉纤维多样性的产生。这些研究将定义用于使动物肌肉谱系多样化的重要调节机制，并鉴于发育机制的强烈进化保护，我们的结果将与包括脊椎动物在内的高等动物（包括脊椎动物）的肌肉形成广泛相关。我们希望我们的基础研究结果最终会导致新的机制和范式，以理解哺乳动物的肌肉如何形成以及肌肉发育和功能如何在患病状态下出现问题。与公共卫生的相关性：这项研究将告诉我们基因如何共同发挥体内的肌肉。由于使苍蝇中肌肉的基因与在包括人类在内的高等动物中起作用的基因非常相似，因此我们的发现将有助于我们了解人类肌肉的形成方式以及身体中的特定肌肉如何以其方式发挥作用。我们预计我们的研究结果将使其他人更好地了解肌肉的形成方式，以及在疾病状况下如何破坏肌肉。