Cell Fate Determination in the Mesoderm of Drosophila

描述（由申请人提供）：对治疗肌肉萎缩的更好疗法的需求正在增长，这是由诸如肌营养不良症的疾病、化疗和发达国家人口快速老龄化驱动的需求。成功的新疗法将产生成肌细胞，这些成肌细胞融合适当的次数并重塑目标肌肉。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，这些特征统称为肌肉的形态。这项计划的目标是将控制身份的基因与肌肉形态的过程联系起来。这将导致对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个非常有效的模型系统，在这项调查中使用，由于独特的遗传，细胞和基因组的方法，它提供。基于已发表的和初步的数据，我们提出，5个转录调节因子，Kruppel，Twist，Apterous，Caupolican和肌肉节段同源框的联合活动，控制外侧肌肉的形态发生。我们将对受每个调节器影响的肌肉属性（大小，形状，方向或附件）进行分类。我们将确定这些因素中的哪些相互调节，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是由这些监管机构在形态发生过程中控制的。最后，我们将开始确定由这些FC身份调节因子调控的靶基因。综合起来，我们就可以看到调控特定形态特征的过程和基因。我们的工作将直接应用于脊椎动物肌肉形态发生和治疗，以及几种人类疾病的潜在机制。例如，两种颅面病症Saethre-Chotzen综合征和Wolf-Hirschhom综合征分别与人TWIST和MSX 1（Msh）有关。此外，已发现人Twist在肿瘤转移中起核心作用。我们在果蝇中对这些调节剂作用的机制和靶点的研究将为这些疾病的根本原因提供深入了解，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.