Tissue Homeostasis through Cell Competition and Compensation

本项目将研究细胞和发育生物学中的一个基本问题，即细胞维持组织健康状态的新机制。健康的细胞监视周围的细胞，诱导生病的细胞死亡，然后补偿健康细胞的生长和分裂，使组织保持相同数量的细胞，所有的细胞都是健康的。这些研究将为这一过程的精细控制如何发生以修复受损组织，以及它如何在衰老组织中发生变化提供新的见解。除了具有科学价值外，该项目还将整合研究和科学教育。所获得的知识将作为课堂陈述的数据，激发学生对科学研究的兴趣。此外，PI将从代表性不足的群体中招募高中和本科学生参与该项目。学生将在分子生物学和遗传学领域进行定向的独立研究，不仅学习基础技术，还学习批判性的科学思维，这将有利于他们未来的职业生涯。PI还将在当地学校进行演示，并将项目相关研究带入本科实验课程。这些活动将促进代表性不足的群体的参与，并对整个社会产生广泛的影响。在他们最近的研究中，PI及其同事发现，在有丝分裂后的果蝇滤泡上皮中，正常细胞通过jnk依赖性的“细胞竞争”在消除异常但有活力的邻居中发挥积极作用，并经历零星的细胞肥大来修复组织。这种“代偿性细胞肥大”（CCH）可能是有丝分裂后组织稳态的一般细胞机制，因为当有丝分裂后滤泡上皮中的一些细胞不能生长到完全大小时，也会诱导这种机制。PI及其同事进一步发现，肥大细胞中胰岛素或胰岛素样生长因子（IGF）样信号（IIS）的过度激活可诱导CCH。在拟议的研究中，他们将确定有丝分裂后细胞竞争和CCH过程的机制。本研究将针对以下具体目的：(1)揭示有丝分裂后细胞竞争中失败者细胞淘汰的机制。在这一目标下，关键问题，如JNK信号是如何在胜利细胞邻近的失败细胞中被激活的，以及这一途径是如何通过凋亡来消除失败细胞的，将得到解决。(2)确定局部组织体积损失诱导CCH的机制。本研究的重点是局部组织体积的变化是如何转化为某些获胜细胞的IIS信号激活的，以及细胞肥大是如何被调节的。他们将测试稳态CCH是由局部组织体积损失引起的张力引起的假设。

This project will study a basic question in cell and developmental biology, a novel mechanism by which cells maintain tissues in a healthy state. Healthy cells monitor their neighbors and induce sick cells to undergo cell death, followed by compensating growth and division of the healthy cells, so that the tissue keeps the same number of cells and all the cells are healthy. These studies will provide new insight into how the fine control of this process occurs to repair damaged tissues, and how it changes in aging tissues. In addition to its scientific merit, the project will also integrate research and science education. The knowledge obtained will be used as data for classroom presentation to stimulate students' interest in scientific research. Furthermore, the PI will recruit high-school and undergraduate students from underrepresented groups to participate in the project. Students will carry out directed independent research in the areas of molecular biology and genetics, and learn not only the basic technology but also critical scientific thinking, which will benefit their future careers. The PI will also present in local schools and will bring the project-related research to an undergraduate experimental course. These activities will promote the participation of underrepresented groups and have a broad impact on society at large.In their recent studies, the PI and colleagues found that, in post-mitotic Drosophila follicular epithelia, normal cells play an active role in eliminating aberrant but viable neighbors through JNK-dependent "cell competition," and undergo sporadic cellular hypertrophy to repair the tissue. This "compensatory cellular hypertrophy" (CCH) is probably a general cellular mechanism for post-mitotic tissue homeostasis, as it is also induced when some cells in the post-mitotic follicular epithelium fail to grow to their full size. The PI and colleagues further found that CCH is induced by hyperactivation of insulin- or IGF (insulin-like growth factor)-like signaling (IIS) in hypertrophic cells. In the proposed study, they will determine the mechanisms underlying post-mitotic cell competition and CCH processes. This research will address the following specific aims: (1) To reveal the mechanisms underlying loser cell elimination in post-mitotic cell competition. Under this aim, crucial questions such as how JNK signaling is activated in winner cells neighboring loser cells, and how this pathway executes its effect to eliminate loser cells via apoptosis, will be addressed. (2) To determine the mechanisms by which loss of local tissue volume induces CCH. This aim focuses on how changes in local tissue volume are translated into IIS signaling activation in certain winner cells, and how cellular hypertrophy is regulated. They will test the hypothesis that homeostatic CCH is induced by tensile forces caused by loss of local tissue volume.