CAREER: Signal processing in the Erk pathway: dynamics, decisions, and development

职业：Erk 通路中的信号处理：动态、决策和发展

基本信息

批准号：
1750663
负责人：
Jared Toettcher
金额：
$ 130.83万
依托单位：
Princeton University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-15 至 2023-03-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1750663&HistoricalAwards=false
关键词：
CAREER Signal processing Erk pathway

项目摘要

One of the most exciting and provocative ideas in modern biology is the notion that cells can be "reprogrammed" and engineered to perform a desired function. Yet the ability to manipulate cellular responses is still quite limited in two key ways. First, researchers have not deciphered the instructions used by cells to adopt a particular response. Second, even if researchers perfectly knew which instructions to provide, they lack the tools to deliver them to a particular cell of interest, at a precise time, without affecting its neighbors. This research will address both of these key challenges by studying a protein, Erk, that plays a fundamental role in organizing cell decisions in all multicellular organisms. This project will rely on a combination of cutting-edge tools: live-cell biosensors to measure natural Erk responses and engineered, light-sensitive proteins to alter Erk activity at precise times and locations in a tissue. This comprehensive understanding of how Erk activity patterns control responses at the cell, tissues, and whole organism scales and how one can alter those patterns to control cell fate. These studies will be integrated with an education plan to train the next generation of quantitative biologists and to foster early exposure to research for historically underrepresented students.The long-term goal of the researcher's lab is to address two fundamental problems in cellular systems biology. How are a small number of highly conserved signaling pathways repurposed in different cell types and organisms to encode information about the external world? Which features of the signals sent by these pathways are sufficient to specify cell-, tissue-, and organism-level phenotypes? Fulfilling these two aims will help to bridge the gap from a static genotype to complex multicellular phenotypes and define the computations that are carried out by the groups of proteins that work together to process cellular information. The research plan is focused on an extensively studied signaling pathway, the Erk pathway, which plays essential roles across eukaryotic organisms. Although the individual proteins comprising the pathway have been thoroughly studied by genetic and biochemical approaches, live-cell Erk biosensors have recently revealed exquisite spatiotemporal patterns of activity: oscillations in individual cells, propagating waves across tissues, and a fast succession of spatial patterns during embryogenesis. The work will dissect these ornate patterns using a combination of quantitative measurements and highly controlled optogenetic inputs that can be used to activate Erk signaling in any spatial or temporal pattern. In particular, the research seeks to: (1) dissect the mechanism that generates pulses of Erk activity in a laboratory model of the epidermis; (2) determine how Erk dynamics control gene expression and cell fate in epidermal cells; and (3) unravel how Erk signaling affects tissue morphogenesis in the developing fly embryo, where exquisite signaling patterns appear over time and in 3D space throughout the organism. The research is complemented by an education plan directed at broadening the early-stage research opportunities available to undergraduates, particularly historically underrepresented students, and at disseminating the tools of quantitative biology and optogenetics to the next generation of cell and developmental biology trainees.The Project is jointly funded by Molecular and Cellular Biosciences and Integrative Organismal Systems, with additional support provided by the Directorate's Rule of Life Venture Fund.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

现代生物学中最令人兴奋和挑衅的想法之一是，可以“重编程”细胞并设计以执行所需功能的概念。然而，操纵细胞反应的能力在两个关键方面仍然非常有限。首先，研究人员尚未破译细胞用于采用特定响应的指令。其次，即使研究人员完全知道要提供的指示，他们也缺乏将它们传递到精确时间的特定细胞的工具，而不会影响其邻居。这项研究将通过研究蛋白质ERK来解决这两个关键挑战，该蛋白在组织所有多细胞生物的细胞决策中起着基本作用。该项目将依靠尖端工具的组合：活细胞生物传感器来测量天然ERK反应和设计的光敏蛋白质，以在精确的时间和组织中的位置改变ERK活性。对ERK活动模式如何控制细胞，组织和整个生物量表的反应以及如何改变这些模式以控制细胞命运的这种全面理解。这些研究将与一项教育计划集成，旨在培训下一代定量生物学家，并促进对历史上代表性不足的学生进行研究的早期研究。研究人员实验室的长期目标是解决蜂窝系统生物学中的两个基本问题。在不同的细胞类型和生物体中，如何重新利用少数高度保守的信号通路来编码有关外部世界的信息？这些途径发送的信号的哪些特征足以指定细胞，组织和生物水平的表型？实现这两个目标将有助于弥合从静态基因型到复杂多细胞表型的差距，并定义由共同工作以处理细胞信息的蛋白质组进行的计算。该研究计划的重点是广泛研究的信号通路ERK途径，ERK途径在真核生物中扮演着重要的作用。尽管通过遗传和生化方法对包含该途径的单个蛋白质进行了彻底研究，但活细胞ERK生物传感器最近揭示了活性的精美时空模式：单个细胞的振荡，在跨组织中传播波浪，以及在胚胎发生过程中的空间模式的快速连续。这项工作将使用定量测量和高度控制的光遗传学输入的组合解剖这些华丽的模式，这些输入可用于在任何空间或时间模式中激活ERK信号传导。特别是，该研究试图：（1）在表皮实验室模型中剖析产生ERK活性脉冲的机制；（2）确定ERK动力学如何控制表皮细胞中的基因表达和细胞命运；（3）揭示ERK信号如何影响发育中的蝇胚中组织形态发生，在该胚胎中，精致的信号传导模式随时间而出现在整个生物体的3D空间中。这项研究的补充是一项旨在扩大本科生（特别是历史上代表性不足的学生）的早期研究机会，并传播定量生物学和光遗传学的工具，向下一代细胞和发育生物学训练者提供。反映了NSF的法定任务，并使用基金会的知识分子优点和更广泛的影响审查标准来评估值得支持。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Engineering combinatorial and dynamic decoders using synthetic immediate-early genes

使用合成的早期基因设计组合和动态解码器

DOI：
10.1038/s42003-020-01171-1
发表时间：
2020
期刊：
Communications Biology
影响因子：
5.9
作者：
Ravindran, Pavithran T.;Wilson, Maxwell Z.;Jena, Siddhartha G.;Toettcher, Jared E.
通讯作者：
Toettcher, Jared E.

Optogenetic control of the Bicoid morphogen reveals fast and slow modes of gap gene regulation.

DOI：
10.1016/j.celrep.2022.110543
发表时间：
2022-03-22
期刊：
CELL REPORTS
影响因子：
8.8
作者：
Singh, Anand P.;Wu, Ping;Ryabichko, Sergey;Raimundo, Joao;Swan, Michael;Wieschaus, Eric;Gregor, Thomas;Toettcher, Jared E.
通讯作者：
Toettcher, Jared E.

Optimizing photoswitchable MEK

DOI：
10.1073/pnas.1912320116
发表时间：
2019-12
期刊：
Proceedings of the National Academy of Sciences
影响因子：
0
作者：
Aleena L. Patel;E. Yeung;S. McGuire;Andrew Y Wu;Jared E. Toettcher;R. Burdine;S. Shvartsman
通讯作者：
Aleena L. Patel;E. Yeung;S. McGuire;Andrew Y Wu;Jared E. Toettcher;R. Burdine;S. Shvartsman

Putting in the Erk: Growth factor signaling and mesoderm morphogenesis

放入 Erk：生长因子信号传导和中胚层形态发生