Genetic regulation of muscle fiber diversity

描述（由申请人提供）：本申请的长期目标是了解个体肌肉如何在体内呈现其独特特征，并确定指导成肌细胞走向这些独特命运的因素。身体中所有的肌肉细胞都有将它们大致分为快纤维或慢纤维的特征，但在纤维身份最初是如何确定的方面，我们还有很多要学习。在这里，我们将使用模型动物果蝇，其成年胸腔的肌肉具有两种不同的表型：驱动飞行的纤维肌肉；管状肌是行走和跳跃所必需的。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因子-2 （MEF2）是这些肌肉模式的重要调节因子，在这项应用中，我们将详细定义MEF2在成人肌肉发育中的功能，并确定MEF2控制纤维模式的基因。我们目前的工作还确定了一些增强因子，这些增强因子的活动仅限于纤维或管状肌肉。我们假设这些增强子的调控因子是特定肌肉特性的关键决定因素，因此我们将确定作用于这些增强子的转录调控因子，并确定它们在肌肉发育和肌纤维多样性产生中的作用。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，并且考虑到发育机制的强进化保守性，我们的研究结果将与包括脊椎动物在内的高等动物肌肉的形成具有广泛的相关性。我们希望我们的基础研究结果将最终导致新的机制和范式，以理解哺乳动物肌肉是如何形成的，以及肌肉的发育和功能是如何在疾病状态下出错的。与公众健康相关：这项研究将告诉我们基因是如何共同作用形成人体肌肉的。由于果蝇的肌肉基因与包括人类在内的高等动物的肌肉基因惊人地相似，我们的发现将帮助我们了解人类肌肉是如何形成的，以及身体中特定肌肉是如何发挥作用的。我们预计，我们的研究结果将使其他人更好地了解肌肉是如何形成的，以及肌肉在疾病条件下是如何被破坏的。

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.