Regulation of cell and organ size in vivo

项目描述（申请人提供）：本项目旨在了解体内组织生长和器官大小的遗传途径。我们实验室之前的研究利用了一种筛选方法，利用发育中的果蝇眼睛中产生的基因嵌合体来识别导致组织过度生长的突变。在筛选中发现的许多突变都是在该资助的前一个资助期间确定的。在本文中，前两个具体目标详细描述了在x染色体筛选中鉴定的两个位点的实验：ovo和HK115。目的1描述了一种识别HK115突变体中突变的开放阅读框的策略，以及确定HK115如何调节组织生长和凋亡的实验。目的2概述了表征卵细胞途径的研究，卵细胞编码一种转录因子调节生长和细胞周期进程。目标3和目标4解决了一种鲜为人知的现象，即细胞竞争，即细胞能够杀死生长较慢的相邻细胞。一种新的筛选方法已经被开发出来，用来识别超级竞争者——使突变细胞能够杀死它们的野生型邻居的突变。在筛选中发现了面包屑中的突变，这是一种顶基极性的调节因子。目标3描述了一种确定碎屑如何在细胞竞争中发挥作用的方法。目标4包括一个广泛的策略，包括一个新的基因筛选，用于识别和表征调节细胞竞争的其他基因。这些研究可能为研究生长在发育过程中是如何被调节的以及肿瘤发展过程中发生的生长异常提供有价值的见解。公共卫生相关性：细胞生长、细胞分裂和存活的精确调控是生物体正常发育所必需的。这些过程的扰动可导致出生异常和癌症。这一建议描述了一种遗传学方法，利用果蝇来提高我们对调节组织生长机制的理解。

DESCRIPTION (provided by applicant): This project is aimed at understanding the genetic pathways that tissue growth and organ size in vivo. Previous studies in our laboratory have utilized a screen that utilizes genetic mosaics generated in the developing Drosophila eye to identify mutations that result in tissue overgrowth. Many of the mutations that have been identified in the screen have been characterized during previous funding periods of this grant. In this proposal, the first two Specific Aims detail experiments to characterize two loci that were identified in the screen of the X-chromosome: ovo and HK115. Aim 1 describes a strategy for identifying the open reading frame that is mutated in the HK115 mutants and experiments to determine how HK115 regulates tissue growth and apoptosis. Aim 2 outlines studies for characterizing the pathway by which ovo, which encodes a transcription factor regulates growth and cell cycle progression. Aims 3 and 4 address a poorly understood phenomenon known as cell competition by which cells are able to kill adjacent cells that grow more slowly. A novel screen has been developed to identify supercompetitors - mutations that enable mutant cells to kill their wild-type neighbors. Mutations in crumbs, a regulator of apicobasal polarity were identified in the screen. Aim 3 describes an approach to determine how crumbs functions with respect to cell competition. Aim 4 consists of a broad strategy, including a new genetic screen, for identifying and characterizing additional genes that regulate cell competition. These studies are likely to provide valuable insights into how growth is regulated during development as well as the growth abnormalities that occur during the development of tumors. PUBLIC HEALTH RELEVANCE: The precise regulation of cell growth, cell division and survival are necessary for the proper development of an organism. Perturbations of these processes can result in birth abnormalities and cancer. This proposal describes a genetic approach, using the fruit fly, to improve our understanding the mechanisms that regulate tissue growth.