Mechanisms Regulating Myoblast Fusion in Drosophila

描述（由申请人提供）：人类和果蝇的肌肉均由成肌细胞融合产生的多核肌纤维组成。然而，调控成肌细胞融合的事件和分子并不清楚。我们的长期目标是了解成肌细胞的融合，特别是创造肌纤维所需的融合事件数量的调节。这个建议的目的是确定关键的细胞和分子机制控制成肌细胞融合的模式生物，果蝇。果蝇和哺乳动物之间肌肉发育的基因和机制的保守性使我们能够使用更简单的果蝇系统来进行相关的发现，用于治疗人类肌肉疾病以及由于衰老和化疗引起的肌肉萎缩。我们的中心假设是，特定的细胞骨架重排是成肌细胞融合的关键。在我们强有力的初步数据的指导下，这一假设将在三个特定的目标进行检验：（1）确定成肌细胞融合的关键细胞骨架重排;（2）确定已知融合基因在调节成肌细胞融合的特定细胞骨架行为中的需求;（3）确定新融合基因在调节成肌细胞融合的特定细胞骨架重排中的作用。根据第一个目标，我们已经开发了新的成像技术，以确定在活的和固定的胚胎成肌细胞融合过程中的细胞骨架重排。我们的初步数据已经确定了几个这样重要的细胞骨架重排。根据第二个目标，我们将测试已知的融合基因与这些细胞骨架重排的关系的影响。我们已经可以将特定基因的活动与特定的细胞骨架重排联系起来。在第三个目标下，我们将通过研究我们已经鉴定的新基因来研究融合过程中细胞骨架变化的机制。我们的工作是有意义的，因为它有望揭示细胞-细胞融合的细胞和分子机制。拟议的研究与公共卫生有关，因为一旦确定或理解了分子参与者及其作用的细胞靶点，就可以开发旨在调节成肌细胞融合的疗法，以促进融合，治疗因衰老或疾病引起的肌肉萎缩。

DESCRIPTION (provided by applicant): Muscles in both humans and Drosophila are composed of multinucleate myofibers that are generated by the fusion of myoblasts. However, the events and molecules that regulate myoblast fusion are not well understood. Our long-term goal is to understand myoblast fusion, and in particular, the regulation of the number of fusion events required to create a muscle fiber. The objective of this proposal is to determine the critical cellular and molecular mechanisms controlling myoblast fusion in the model organism, Drosophila melanogaster. The conservation of genes and mechanisms in muscle development between Drosophila and mammals allows us to use the simpler Drosophila system to make relevant discoveries for treatments of human muscular diseases and of muscle wasting due to aging and chemotherapies. Our central hypothesis in this proposal is that specific cytoskeletal rearrangements are critical for myoblast fusion. Guided by our strong preliminary data, this hypothesis will be tested in three specific aims: (1) Identify the critical cytoskeletal rearrangements that underlie myoblast fusion; (2) Determine the requirement of known fusion genes in regulating specific cytoskeletal behaviors underlying myoblast fusion; and (3) Identify the role of new fusion genes in regulating the specific cytoskeletal rearrangements critical for myoblast fusion. Under the first aim, we have developed novel imaging techniques to identify cytoskeletal rearrangements during myoblast fusion in living and fixed embryos. Our preliminary data has pinpointed several such important cytoskeletal rearrangements. Under the second aim, we will test the impact of known fusion genes in relationship to these cytoskeletal rearrangements. Already we can link specific genes' activities to specific cytoskeletal rearrangements. Under the third aim we will investigate the mechanisms underlying the cytoskeletal changes during fusion by examining novel genes that we have identified. Our work is significant because it expected to reveal the cellular and molecular mechanisms underlying cell-cell fusion. The proposed research is relevant to public health because once the molecular players and the cellular targets of their action are identified or understood, therapies designed to regulate myoblast fusion can be developed to promote fusion for the treatment of muscle wasting due to aging or disease.