Cell competition and stem cell parasitism in a basal chordate

基底脊索动物的细胞竞争和干细胞寄生

基本信息

批准号：
10017299
负责人：
Anthony W De Tomaso
金额：
$ 30.27万
依托单位：
UNIVERSITY OF CALIFORNIA SANTA BARBARA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10017299
关键词：
Adult Affect Animal Model Area Autocrine Communication Biological Assay Biology Cells Chordata Clinical Complex Cues Development Developmental Process Disease Embryonic Development Genotype Germ Cells Growth Health Heritability Homeostasis Homing Human Hydroxyeicosatetraenoic Acids In Situ In Vitro Individual Life Lipids Malignant Neoplasms Modeling Molecular Natural regeneration Nature Normal Cell Organ Organism Pathologic Processes Pathway interactions Phenotype Play Population Process Production Property Quality Control Regenerative Medicine Resolution Resources Rest Role Signal Transduction Testing Tissues Transplantation Tumor Suppressor Proteins Urochordata Variant ascidian base cell motility developmental disease fitness germline stem cells in vivo innovation life history loss of function migration neoplastic cell novel novel strategies parasitism polarized cell progenitor response self-renewal sensor sphingosine 1-phosphate stem cell biology stem cell population stem cells trait tumor initiation tumor progression

项目摘要

ABSTRACT Cell competition is a process that compares the relative fitness of progenitor cells, resulting in `winners', which contribute further to development, and `losers', which are excluded, and is likely a universal quality control process that contributes to the fitness of an individual. Cell competition may also be involved in cancer, during which cells become `supercompetitors', subsequently outcompeting normal cells for resources and growth. Thus cell competition is a widespread phenomenon that has both developmental and disease relevance. However, the mechanisms underlying cell competition are not well understood. What is a sensor of fitness? Are there common regulatory mechanisms? How do the mechanisms underlying competition break down during disease? We are utilizing the unique biology of a model organism that will allow us to study these questions. Our model is the colonial tunicate, Botryllus schlosseri, which has germline stem cells (GSCs) that have genetically determined competitive phenotypes, with winner cells outcompeting loser cells. We can exploit the natural phenotypic variation present in our lab reared populations to characterize the mechanisms underlying cell competition. We can purify these cells to near homogeneity using FACS, transplant them, and quantify their contribution to gamete development. We have recently found that competitive differences may be in differences in migratory ability, specifically how cells responds to lipid signaling. In Aim 1, we will build upon these recent results, using both in vitro and in vivo assays developed in our lab to dissect the response of GSCs to lipid signaling. In Aim 2, we will take an unbiased approach, characterizing germ cell migration and development using different competitive genotypes developed in our lab, both in situ and during competition, following reciprocal transplantations, and utilize this natural phenotypic variation to pinpoint where competition may occur. Completion of the proposed aims will advance our understanding of the mechanisms which underlie competitive interactions between stem cells, which is becoming increasingly appreciated as a fundamental and conserved process in multicellular development, and may be important for instructing clinical regeneration using stem cells. When inappropriately activated, these competitive mechanisms may also be responsible for escape of normal growth control during cancer progression. Botryllus is a unique organism that allows novel approaches to study conserved molecular mechanisms of cell competition that underlie development, regenerative medicine, and cancer progression, areas of great importance for human health.

抽象的细胞竞争是一个比较祖细胞相对适应性的过程，导致 “获奖者”，进一步有助于发展，而“失败者”被排除在外，很可能是通用质量控制过程有助于个人的适应性。细胞竞争可能还参与癌症，在此期间，细胞成为“超级竞争者”，随后胜过正常的资源和增长细胞。因此，细胞竞争是一种广泛的现象发育和疾病相关。但是，细胞竞争的基础机制是不太了解。什么是健身传感器？有常见的监管机制吗？怎么办疾病期间竞争的基础机制分解了吗？我们正在利用模型生物的独特生物学，这将使我们能够研究这些问题。我们的模型是殖民剪裁，botryllus schlosseri，其具有生殖干细胞（GSC），可具有遗传确定的竞争表型，赢家细胞胜过失败者细胞。我们可以利用我们实验室饲养人群中存在的自然表型变异来表征细胞竞争的基础机制。我们可以使用FACS将这些细胞纯化为几乎均匀性，移植它们，并量化它们对配子发展的贡献。我们最近发现竞争差异可能在迁移能力上存在差异，特别是细胞如何反应脂质信号传导。在AIM 1中，我们将使用体外和体内测定法以这些最新结果为基础在我们的实验室中开发以剖析GSC对脂质信号的反应。在AIM 2中，我们将接受公正的方法，表征生殖细胞迁移和开发使用不同的竞争在我们的实验室中开发的基因型，无论是原地还是在竞争期间，在倒数之后移植，并利用这种自然表型变化来查明可能发生竞争的地方。拟议目标的完成将提高我们对基于机制的理解干细胞之间的竞争相互作用，作为一个多细胞开发中的基本和保守过程，对于使用干细胞指导临床再生。当不恰当地激活这些竞争力时机制也可能负责癌症进展过程中正常生长控制的逃脱。 botryllus是一种独特的生物，允许新的方法研究保守的分子基于开发，再生医学和癌症的细胞竞争机制进展，对人类健康非常重要的领域。