Tissue Homeostasis through Cell Competition and Compensation

这个项目将研究细胞和发育生物学中的一个基本问题，即细胞维持组织处于健康状态的一种新机制。健康细胞监测它们的邻居，诱导患病细胞经历细胞死亡，然后补偿健康细胞的生长和分裂，使组织保持相同的细胞数量，所有细胞都是健康的。这些研究将为精细控制这一过程以修复受损组织以及它如何在老化组织中发生变化提供新的见解。除了其科学价值，该项目还将整合研究和科学教育。所获得的知识将被用作课堂演示的数据，以激发学生对科学研究的兴趣。此外，国际学生联合会将从代表性不足的群体中招募高中生和本科生参与该项目。学生将在分子生物学和遗传学领域开展有针对性的自主研究，不仅学习基础技术，还学习批判性科学思维，这将有利于他们未来的职业生涯。PI还将出现在当地学校，并将把与项目相关的研究带入本科实验课程。这些活动将促进未被充分代表的群体的参与，并在广泛的社会中产生广泛的影响。在他们最近的研究中，PI和他的同事发现，在有丝分裂后的果蝇毛囊上皮中，正常细胞通过JNK依赖的“细胞竞争”在消除变异但存活的邻居方面发挥积极作用，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动态平衡的一般细胞机制，因为它也是当有丝分裂后滤泡上皮中的一些细胞无法生长到其全部大小时诱导的。PI和他的同事进一步发现，CCH是由肥大细胞中胰岛素或IGF(胰岛素样生长因子)样信号(IIS)的过度激活引起的。在这项拟议的研究中，他们将确定有丝分裂后细胞竞争和CCH过程的潜在机制。这项研究将致力于以下具体目标：(1)揭示有丝分裂后细胞竞争中失败细胞消除的机制。在这一目标下，关键的问题，如JNK信号如何在邻近失败者细胞的胜利者细胞中被激活，以及这一途径如何发挥其通过凋亡消除失败者细胞的作用，将被解决。(2)探讨局部组织体积丢失导致CCH的机制。这一目标集中在局部组织体积的变化如何转化为某些获胜者细胞中IIS信号的激活，以及细胞肥大是如何被调控的。他们将检验这一假设，即体内平衡性CCH是由局部组织体积损失引起的张力引起的。

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.