Regulation of Cell and Organ Size in Vivo

描述（由申请人提供）：在生物体的发育过程中，大多数组织在发育过程中达到可预测的大小。以时空方式调节单个细胞的生长、增殖和存活以达到最终大小的机制 和器官的形状都知之甚少。我们的实验室已经在果蝇中使用了遗传方法来识别调节细胞增殖和器官大小的基因。在以前的资助周期中表征的基因包括Hippo途径的几个组成部分，群岛，它编码一种泛素连接酶，靶向细胞周期蛋白E和Myc降解以及Tsc 1和Tsc 2基因。除了在发育过程中调节生长外，这些基因也是令人感兴趣的，因为它们的人类直系同源物在几种类型的癌症中突变。 我们最近发现，喷火基因，它编码的泛素连接酶，作为一个负调节组织生长和调节细胞表面的原钙粘蛋白脂肪的水平。此外，喷火和脂肪似乎共同定位在顶端膜和囊泡的人口。我们建议阐明喷火调节脂肪定位和功能的机制。这将通过使用利用质谱法的方法鉴定喷火的底物以及通过进行旨在鉴定喷火的调节剂和效应物的遗传筛选来实现。我们还将测试喷火是否调节其他信号通路。 我们还发现，相邻细胞之间自噬调节剂Atg2表达水平的差异可以影响克隆边界附近的组织生长和细胞存活。我们将确定这种现象是否是由于自噬在细胞竞争或类似过程中的作用，或者，Atg基因的一个子集是否通过自噬非依赖性途径在调节细胞增殖和存活中发挥作用。

DESCRIPTION (provided by applicant): During the development of an organism, most tissues achieve a predictable size during development. The mechanisms that regulate the growth, proliferation and survival of individual cells in a spatiotemporal manner to achieve the final size and shape of the organ are poorly understood. Our laboratory has used a genetic approach in the fruit fly Drosophila melanogaster to identify genes that regulate cell proliferation and organ size. Among the genes characterized in previous funding cycles include several components of the Hippo pathway, archipelago, which encodes a ubiquitin ligase that targets Cyclin E and Myc for degradation and the Tsc1 and Tsc2 genes. In addition to regulating growth during development, these genes are of interest because their human orthologs are mutated in several types of cancer. We have recently found that the spitfire gene, which encodes a ubiquitin ligase, functions as a negative regulator of tissue growth and regulates the levels of the protocadherin Fat at the cell surface. Furthermore Spitfire and Fat appear to co-localize at the apical membrane and in a population of vesicles. We propose to elucidate the mechanism by which Spitfire regulates Fat localization and function. This will be achieved by identifying substrates of Spitfire using approaches that utilize mass spectrometry as well as by conducting genetic screens aimed at identifying regulators and effectors of Spitfire. We will also test whether Spitfire regulates other signaling pathways. We have also found that differences in expression levels of the autophagy regulator Atg2 between neighboring cells can influence tissue growth and cell survival near the clonal boundary. We will determine whether this phenomenon is due to a role for autophagy in cell-competition or similar process or, alternatively, whether a subset of Atg genes has a role in regulating cell proliferation and survival via an autophagy-independent pathway.