A novel signaling pathway for tissue homeostasis

描述（由申请人提供）：细胞如何交流以协调其生长是生物学中的一个基本问题，对医学和健康的许多方面都很重要，包括器官再生和移植，干细胞生物学和癌症。在这里，我们解决了我们最近发现的信号通路如何在发育和重塑组织中细胞之间的竞争性相互作用中发挥作用，其中正常存活的细胞在与代谢率较高的“赢家”细胞相邻时被杀死和消除。我们建议在果蝇中进行实验，以利用强大的遗传和分子工具，这是无与伦比的高等动物。我们将使用突变体的遗传分析，体细胞克隆技术和分子分析来实现两个具体目标：目的1，研究“失败者”细胞中信号通路的机制作用，并发现作为细胞竞争效应器的信号通路的靶基因，目的2，以确定推定的配体如何介导“失败者”和“赢家”细胞之间的通信，并导致失败者细胞中信号通路的激活。这些研究将揭示生长中的上皮细胞之间相互作用的潜在机制，这可能对改善人类的健康和护理有价值。此外，它们将扩大我们对生长过程中细胞间通讯基本方面的理解。 公共卫生相关性：我们以前的工作使用果蝇作为一个模型系统已经证明，当它们以不同的代谢率生长时，相邻细胞之间的竞争被诱导。这个过程确保了组织在生长和发育过程中的可塑性。我们最近的实验表明，在竞争过程中有一种新的信号通路，在这里，我们的目标是利用果蝇分子遗传学无与伦比的力量来了解它在竞争中所涉及的细胞事件中的作用，如过度生长，细胞死亡和细胞间通讯。细胞竞争与癌症的早期阶段具有显着的相似性，因此我们预计这项工作将有助于识别区分早期癌细胞与其野生型邻居的标志物。此外，它将增强我们对组织可塑性和适应性选择机制的认识。此外，我们对生长过程中细胞通讯的基本生物学特性的理解将得到扩展。

DESCRIPTION (provided by applicant): How cells communicate to coordinate their growth is a fundamental question in biology that is important to many aspects of medicine and health, including organ regeneration and transplantation, stem cell biology, and cancer. Here we address how a signaling pathway we recently uncovered functions during competitive interactions between cells in developing and remodeling tissues, in which normally viable cells are killed and eliminated when they grow next to "winner" cells with higher metabolic rates. We propose experiments in Drosophila to take advantage of the powerful genetic and molecular tools available, which are unparalleled in higher animals. We will use genetic analysis of mutants, somatic clonal techniques, and molecular analysis to achieve two specific aims: Aim 1, to investigate the mechanistic role of the signaling pathway in "loser" cells and discover target genes of the pathway that function as effectors of cell competition, and Aim 2, to determine how a putative ligand mediates communication between "loser" and "winner" cells and leads to activation of the signaling pathway in loser cells. These studies will reveal mechanisms underlying interactions between cells in growing epithelia that may be valuable for improving the health and care of humans. In addition, they will expand our understanding of fundamental aspects of cell-cell communication during growth. PUBLIC HEALTH RELEVANCE: Our previous work using Drosophila as a model system has demonstrated that competition is induced between neighboring cells when they grow with different metabolic rates. This process ensures tissue plasticity during growth and development. Our recent experiments have implicated a novel signaling pathway in the competition process, and here we aim to use the unparalleled power of Drosophila molecular genetics to understand its role in the cellular events involved in competition, such as overgrowth, cell death and cell-cell communication. Cell competition has remarkable similarities to the early stages of cancer, thus we anticipate that this work will aid in the identification of markers distinguishing early cancer cells from their wildtype neighbors. In addition, it will enhance our knowledge of mechanisms of tissue plasticity and fitness selection. Furthermore, our understanding of the basic biological properties of cell communication during growth will be expanded.