Cell Fate Determination in the Mesoderm of Drosophila

描述(申请人提供)：对治疗肌肉萎缩的更好疗法的需求正在增长，这种需求是由肌肉营养不良症等疾病、化疗和发达国家迅速老龄化的人口推动的。成功的新疗法将产生成肌细胞，这些成肌细胞可以融合适当的次数，重塑目标肌肉。然而，开发这些疗法的一个障碍是缺少关于成肌细胞如何将其身份信息转化为肌肉的大小、形状、方向和与周围细胞的关联的关键信息，即统称为肌肉形态的特征。这项提议的目标是将控制身份的基因与阐述肌肉形态的过程联系起来。这将导致对在发育和疾病期间获得大小和形状至关重要的基因和过程的理解。果蝇肌肉形态发生是一种非常有效的模型系统，用于这项研究，因为它提供了独特的遗传，细胞和基因组方法。根据已发表的和初步的数据，我们认为Kruppel、Twist、Apterous、Caupolica和Muscle Segment Homeobox这5种转录调控因子的联合作用控制着侧肌的形态发生。我们将对每个调节器影响的肌肉属性(大小、形状、方向或附着)进行分类。我们将确定这些因素中的哪些相互调节，以及哪些协同调节肌肉形态发生的不同方面。然后，我们将确定FC细胞行为的哪些方面在形态发生过程中由这些调节因子控制。最后，我们将开始识别受这些FC身份调节器调控的靶基因。综上所述，将出现一幅调控特定形态特征的过程和基因的图景。我们的工作将直接应用于脊椎动物肌肉的形态发生和治疗，以及几种人类疾病的潜在机制。例如，两种颅面部疾病，Saethre-Chotzen综合征和Wolf-Hirschhom综合征，分别与人类扭曲和MSX1(MSH)有关。此外，人类Twist已被发现在肿瘤转移中发挥核心作用。我们在果蝇中所做的关于这些调节器作用的机制和靶点的工作将提供对这些疾病的潜在原因的洞察，并将有助于揭示潜在的治疗方法。

DESCRIPTION (provided by applicant): The need for better therapies to treat muscle wasting is growing, a need driven by diseases such as muscular dystrophy, by chemotherapies and by the rapidly aging populations of the developed world. Successful new therapies will generate myoblasts that fuse the appropriate number of times and reshape the targeted muscles. A barrier to developing those therapies, however, is the missing critical information about how myoblasts translate their identity information into a muscle's size, shape, orientation and association with surrounding cells, i.e., characteristics collectively called a muscle's morphology. The goal of this proposal is to connect the genes that control identity to the processes that elaborate the muscle morphology. This will result in an understanding the genes and processes critical to acquisition of size and shape during both development and disease. Drosophila muscle morphogenesis is a highly effective model system to use in this investigation, due to the unique genetic, cellular, and genomic approaches that it affords. Based on published and preliminary data, we propose that the combined activities of 5 transcriptional regulators, Kruppel, Twist, Apterous, Caupolican, and Muscle Segment Homeobox, control the morphogenesis of the lateral muscles. We will categorize the muscle attributes (size, shape, orientation or attachment) that are affected by each regulator. We will determine which of these factors regulate each other and which collaborate to regulate distinct aspects of muscle morphogenesis. We then will determine which aspects of FC cellular behavior are controlled by these regulators during morphogenesis. Lastly, we will begin to identify target genes regulated by these FC identity regulators. Taken together, a picture will emerge of the processes and the genes that regulate specific morphological characteristics. Our work will have direct application to vertebrate muscle morphogenesis and therapies, and to the mechanisms underlying several human diseases. For example, two cranial-facial disorders, Saethre-Chotzen syndrome and Wolf-Hirschhom Syndrome, have been linked to human TWIST and MSXl(Msh), respectively. Additionally, human Twist has been found to play a central role in tumor metastasis. Our work in Drosophila on the mechanisms and targets of these regulators' action will provide insight as to the underlying causes of these diseases and will help to reveal potential therapies.