The Role of Extrusion in Controlling Epithelial Homeostasis

挤压在控制上皮稳态中的作用

基本信息

批准号：
8572960
负责人：
Jody Snow Rosenblatt
金额：
$ 7.95万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8572960
关键词：
Antimitotic Agents Aphidicolin Apoptosis Area Asthma Binding Biomedical Engineering Candidate Disease Gene Carcinoma Cell Count Cell Cycle Cell Cycle Progression Cell Death Cell Proliferation Cell division Cells Cessation of life Crowding Death Rate Development Devices Disease Epithelial Epithelial Cells Epithelium Equilibrium Event G0 Phase G2 Phase Gadolinium Grant Growth Heart Homeostasis Hour Kinetics Lead Link Literature Mechanics Mediator of activation protein Membrane Methods Microtubules Mitosis Modeling Molecular Morphogenesis Organ Pathway interactions Phosphorylation Population Process Production Proliferating Proteins Proteomics Reporter Research Role S Phase Semaphorin-3A Signal Transduction Solid Neoplasm Staging Stretching Testing Translating Two-Dimensional Gel Electrophoresis Well in self Wound Healing Zebrafish aurora kinase base cell growth gadolinium oxide gel electrophoresis in vivo inhibitor/antagonist innovation interdisciplinary approach migration monolayer mutant novel parent grant prevent public health relevance research study response tool tumor wound

项目摘要

DESCRIPTION (provided by applicant): The role of cell stretch for inducing proliferation in epithelia provide a protective barrier for the organs they encase; yet cells comprising this barrie are constantly renewed via cell death (apoptosis) and division. Surprisingly little is known about what triggers cells to naturally divide or die or how the number of cells dying and dividing are balanced during homeostasis. If the death rate becomes higher, barrier function diseases such as asthma may result and if the division rate is higher, solid tumors may result. Previously, we found that epithelia match cell death with cell division mechanically through crowding. Epithelial crowding forces from cells accumulating through division and migration act to shove cells out, through a process I discovered termed cell extrusion. Blocking any step of the crowding-induced extrusion pathway that we defined leads to epidermal masses in zebrafish, confirming its critical role for controlling epithelial cell turnover in vivo. While the parent grant investigated how too many cells, manifested by cell crowding, can lead to extrusion-dependent cell death, here, we examine how too few cells within an epithelium, manifested by cell stretching, can lead to production of more cells by cell division. Cell stretching during developmental morphogenesis or wound healing cells frequently occurs prior to a wave of proliferation. We recently found that stretching contact-inhibited epithelial monolayers leads to rapid cell proliferation (within one hour), independently of wound or developmental signals. Because mitosis occurs so rapidly, we predict that these cells initiate division from the G2 phase of the cell cycle, despite starting frm a state usually associated with quiescence. Gadolinium addition block mitosis following stretch, suggesting that stretch-activated channels translate stretch into mitosis. To understand how stretch translates into mitogenic signaling, we will test the following in this revision grant: 1) est from which point(s) in the cell cycle cells initiate proliferation following stretch and 2) identif signals that translate cell stretch into proliferation by testing candidates from the literature an a proteomic screen. Once we identify how stretch activates cells to proliferate, we will test if this same signaling regulates division during normal homeostasis. If so, cell growth could similarly cause stretching of the membrane to trigger mitosis and reveal the elusive link between cell growth and division. Having developed many tools in our parent grant, we feel we are well poised to make rapid strides in identifying this fundamental pathway for regulating cell division. The proposed research is innovative because it examines a novel mechanism for how epithelial cells maintain homeostatic cell numbers, which may also reveal how cells link growth with division. It also uses multidisciplinary approaches, including a zebrafish epidermal model we developed to study epithelia and a cell stretch device we developed with a bioengineer. The proposal is medically significant because misregulation of epithelial homeostasis is likely at the heart of most solid tumor formation and barrier function diseases.

描述（由申请人提供）：细胞伸展在诱导上皮细胞增殖中的作用为它们所包围的器官提供了保护屏障；然而，构成这个屏障的细胞通过细胞死亡（细胞凋亡）和分裂不断更新。令人惊讶的是，对于什么触发细胞自然分裂或死亡，或者细胞死亡和分裂的数量在体内平衡过程中如何平衡，人们知之甚少。如果死亡率变高，可能会导致哮喘等屏障功能疾病，如果分裂率变高，可能会导致实体瘤。此前，我们发现上皮细胞通过拥挤机制将细胞死亡与细胞分裂相匹配。细胞通过分裂和迁移积累的上皮拥挤力将细胞推出去，通过我发现的称为细胞挤出的过程。阻断我们定义的拥挤诱导的挤压途径的任何步骤都会导致斑马鱼表皮肿块，证实其在控制体内上皮细胞更新方面的关键作用。虽然母基金研究了细胞过多（表现为细胞拥挤）如何导致挤压依赖性细胞死亡，但在这里，我们研究了上皮内细胞过少（表现为细胞拉伸）如何导致细胞产生更多细胞分配。发育形态发生或伤口愈合细胞过程中的细胞拉伸经常发生在增殖波之前。我们最近发现，拉伸接触抑制的上皮单层会导致细胞快速增殖（一小时内），而与伤口或发育信号无关。由于有丝分裂发生得如此之快，我们预测这些细胞从细胞周期的 G2 期开始分裂，尽管是从通常与静止相关的状态开始的。添加钆会阻止拉伸后的有丝分裂，这表明拉伸激活的通道将拉伸转化为有丝分裂。为了了解拉伸如何转化为有丝分裂信号，我们将在本次修订资助中测试以下内容：1) est 从细胞周期中细胞在拉伸后的哪个点开始增殖，2) 通过测试识别将细胞拉伸转化为增殖的信号来自文献和蛋白质组筛选的候选者。一旦我们确定了拉伸如何激活细胞增殖，我们将测试这是否相同的信号在正常稳态期间调节分裂。如果是这样，细胞生长同样可能导致细胞膜拉伸，引发有丝分裂，并揭示细胞生长和分裂之间难以捉摸的联系。我们在母公司资助下开发了许多工具，我们认为我们已经做好准备，在确定调节细胞分裂的基本途径方面取得快速进展。拟议的研究具有创新性，因为它研究了上皮细胞如何维持细胞数量稳态的新机制，这也可能揭示细胞如何将生长与分裂联系起来。它还使用多学科方法，包括我们开发的用于研究上皮细胞的斑马鱼表皮模型以及我们与生物工程师开发的细胞拉伸装置。该提议具有医学意义，因为上皮稳态的失调可能是大多数实体瘤形成和屏障功能疾病的核心。