CAREER: Emergence of Population Diversity from Stem Cell Decision Making in Asexual Planarians

职业：无性涡虫干细胞决策中种群多样性的出现

• 批准号: 1555109
• 负责人: Eva-Maria Collins
• 金额: $ 85万
• 依托单位: University of California-San Diego
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1555109&HistoricalAwards=false
• 关键词: CAREER; Emergence; Population; Diversity; Stem

Diversity of individuals is indispensable for population survival and evolution. This CAREER project examines how diversity can emerge from decision making of individual cells in a multicellular regenerative organism. Freshwater planarians are famous for their regenerative capabilities that are based on a large number of adult pluripotent stem cells (ASCs). These ASCs allow them to reproduce by binary fission, thus creating a clonal population and raising the question of how this species is able to create sufficient diversity to survive on evolutionary time scales. Using tools from statistical physics the PI recently demonstrated that reproduction is largely random, but that reproductive patterns exist whose molecular and physical determinants remain to be investigated. This project aims at testing the hypothesis that population diversity arises from a joint effect of the specifics of planarian reproduction mechanics and epigenetic diversity of ASCs in individual worms. The PI will integrate the research objectives of this proposal into three educational initiatives, which focus on "learning through research" and long-term engagement of students: (1) The PI is establishing a partnership with Vista Magnet Middle school that allows 6th graders to work together with her lab on research projects throughout the school year. (2) The PI will continue her efforts toward participation of high school students in research. In particular, she will continue to enable students from Torrey Pines High School to engage in research in her lab throughout the year, which allows them to design and execute their own science projects. (3) The PI will continue her efforts in promoting undergraduate research, in her own group as well as through a new research-centered, quantitative biology laboratory course that she has developed. The course will launch in 2016 and is currently for incoming biology freshmen only. In the context of this proposal, the PI will widen the student population to physics freshmen by adding more physics to the curriculum, and thus create a truly interdisciplinary research-driven laboratory course at the interface of biology and physics in terms of content and student population.How cellular decision-making causes specific phenotypes in a population has received a lot of attention in the context of single celled organisms, but less is known about how epigenetic inheritance affects population diversity in multicellular organisms. This study will close this knowledge gap using planarians and a unique experimental setup, whereby thousands of individual reproductive events have already been recorded and form the statistical framework for the PI's studies on the population level. The PI's strategy is to (1) test the hypothesis that within individual planarians, ASCs are differentially distributed, in terms of spatial orientation and/or molecular and cellular characteristics (division and death rates, genetic and epigenetic diversity) through quantification of ASC localization, cellular dynamics, and single cell sequencing, (2) investigate the biomechanics of asexual reproduction to understand how resources get distributed among offspring using traction force measurements and time-lapse imaging, and (3) develop a mathematical model based on the cellular and organismal level experimental data to predict population level phenotypic diversity. The model will be tested by comparing its predictions with existing experimental data and the reproductive patterns of specially designed founder individuals in which all cells are known to originate from a single ASC, through RNA-seq and statistical analysis. Together, these approaches will allow the PI to test the hypothesis that spatial epigenetic heterogeneity of stem cells in individuals combined with a stochastic reproduction mechanism determine intraspecies phenotypic differences on the population level, which will be measured in terms of reproductive behaviors. The proposed work will shed new light onto the role of transgenerational epigenetic inheritance for the evolutionary success of asexual multicellular life. On a broader level, stem cell decision-making is currently receiving considerable attention because an understanding of how stem cells switch states stochastically and in response to environmental cues is indispensable for successful stem cell therapies.This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Cellular Cluster in the Division of Molecular and Cellular Biosciences

个人的多样性对于人口生存和进化是必不可少的。该职业项目研究了多样性在多细胞再生生物中的单个细胞的决策中如何出现。淡水平面人以其再生能力而闻名，这些能力基于大量的成年多能干细胞（ASC）。这些ASC允许它们通过二元裂变繁殖，从而产生克隆人群，并提出一个问题，即该物种如何能够创造足够的多样性以在进化时尺度上生存。使用统计物理学的工具，PI最近证明了繁殖基本是随机的，但是存在其分子和物理决定因素的生殖模式仍有待研究。该项目旨在检验以下假设：种群多样性源于平面生殖力学的细节和ASC在单个蠕虫中的表观遗传多样性的共同作用。 PI将将该提案的研究目标整合到三个教育计划中，这些计划的重点是“通过研究”和学生的长期参与：（1）PI与Vista Magnet中学建立了合作伙伴关系，允许六年级学生在整个学年中与她的实验室合作。 （2）PI将继续为高中生参与研究而努力。特别是，她将继续使托里·派恩斯高中的学生全年在她的实验室中进行研究，这使他们能够设计和执行自己的科学项目。 （3）PI将继续她自己的小组以及以研究为中心的定量生物学实验室课程来促进本科研究的努力。该课程将于2016年启动，目前仅供进入生物学新生。在该提议的背景下，PI将通过向课程中添加更多的物理学来扩大学生的新生，从而在生物学和物理学的界面上创建一个真正的跨学科研究驱动的实验室课程，以内容和学生人数的范围内。细胞的决策在人群中引起了较少的细胞素养，但较少的人群在众多的范围内却属于众多的人群，而众多的人是在范围内的遗传，而众所周知的是，众所周知的遗产是如何属于的。影响多细胞生物的种群多样性。这项研究将使用平面主义者和独特的实验设置来缩小这一知识差距，该设置已经记录了数千个个人生殖事件，并构成了PI在人群水平上研究的统计框架。 PI的策略是（1）检验以下假设：在单个平面主义者中，ASC在空间取向以及/或分子和细胞特征（分裂和死亡率，遗传和表观遗传多样性）方面通过量化ASC定位，细胞测序，（2）进行外部的效能（2），（2）通过量化的生物机能来研究ASEX的生物机能中的分布，从而差异分布。测量和延时成像，以及（3）基于细胞和有机水平的实验数据开发数学模型，以预测种群水平的表型多样性。该模型将通过将其预测与现有的实验数据和专门设计的创始人个体的生殖模式进行比较来进行测试，其中所有细胞均通过RNA-Seq和统计分析源自单个ASC。这些方法总之将使PI能够检验以下假设：个体中干细胞的空间表观遗传异质性与随机生殖机制相结合确定种群内的种群表型在种群水平上的表型差异，这将根据生殖行为来衡量。拟议的工作将为无性多细胞生命的进化成功而发明新的灯光介绍了转世表观遗传遗传的作用。在更广泛的水平上，干细胞决策目前正在引起非常关注的关注，因为了解干细胞如何随机切换状态以及对环境提示的响应对于成功的干细胞疗法是必不可少的。该项目由物理学的物理学计划与分子和细胞生物学生物科学措施的分工中的生命系统计划共同支持。