A novel signaling pathway for tissue homeostasis

描述（由申请人提供）：细胞如何沟通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，我们讨论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起作用，在这种相互作用中，正常存活的细胞在与具有更高代谢率的“赢家”细胞相邻生长时被杀死和消除。我们建议在果蝇身上进行实验，以利用强大的遗传和分子工具，这在高等动物中是无与伦比的。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特定目标：目标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；目标2，确定一个假定的配体如何介导“失败者”和“胜利者”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，它们将扩展我们对生长过程中细胞-细胞通讯的基本方面的理解。

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.