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

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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.