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，并确定将成肌细胞导向这些独特命运的因素。身体中的所有肌肉细胞都具有将其大致分类为快纤维或慢纤维的特征，但就纤维身份最初是如何确定的而言，我们仍然有很多东西要学习。在这里，我们将使用模式动物果蝇，其中成年人胸部的肌肉呈现两种不同的表型：驱动飞行的纤维肌和行走和跳跃所需的管状肌。到目前为止，我们的研究已经确定了肌源性因子肌细胞增强因子-2（MEF 2）作为这些肌肉图案化的重要调节因子，在本申请中，我们将详细定义MEF 2在成人肌肉发育中的功能，并确定MEF 2控制纤维图案化的基因。我们目前的工作还确定了一些增强子元件，其显示的活动，这是有限的纤维或管状肌肉。我们认为这些增强子的调节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节子，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控机制，并且鉴于发育机制中的强进化保守性，我们的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如何形成以及肌肉发育和功能在疾病状态下如何出错。与公共卫生的相关性：这项研究将告诉我们基因是如何共同作用来制造身体肌肉的。由于在苍蝇中制造肌肉的基因与包括人类在内的高等动物中发挥作用的基因惊人地相似，我们的发现将有助于我们了解人类肌肉是如何形成的，以及身体中特定肌肉的功能如何。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，以及在疾病条件下肌肉是如何被破坏的。

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.