Unraveling the propagation and repercussions of localized perturbations within tissues

这项提议的目的是揭示信号在上皮组织细胞之间传递的重要性，上皮组织构成了大多数动物器官的内层。这种交流对于维持组织健康、伤口愈合以及对感染和癌症做出反应至关重要。该项目将采用实验和建模方法的多学科结合，并将为教育、培训和公众参与提供机会。这些具有更广泛影响的活动包括：1)开发一门课程，让学生学习多细胞相互作用；2)为下一代科学家提供跨学科培训；3)允许本科生暑期实习，以获得研究经验；4)为公民科学家创建有关该主题的网络模块；5)开发与合成生物学和细胞间通信相关的博物馆展览。该项目旨在定量了解组织中局部变化如何传播和影响组织信号和生理。特别是，使用综合的实验和计算方法，我们将研究cAMP/PKA， Ca2+和ERK信号如何在单个上皮细胞内协调，以及这些途径发出的信号如何在组织中从一个细胞传播到其他细胞。将开发光遗传学工具，在组织内指定的单个细胞中对这些途径进行空间和时间上的精确扰动，然后测量在扰动启动的发送细胞以及感知传播扰动的接收细胞中产生的信号传导和转录活动。这种扰动的突发性表型影响，如细胞流动性，将被评估。为了组织和解释数据，概括发现，并设计最大限度地了解实验，将构建数学模型，该模型将独特地考虑组织几何形状和空间维度和异质性对细胞群内相互作用的影响。这种多学科方法将允许对细胞群落协作的基本原则和局部扰动传播和影响组织生理学的方式产生定量理解。该项目由分子和细胞生物科学部的系统和合成生物学项目资助。

The goal of this proposal is to uncover how important signals travel between cells in epithelial tissues that form the lining of most animal organs. This communication is essential for maintaining healthy tissues, wound healing, and responding to infection and cancer. The project will employ a multidisciplinary combination of experimental and modeling approaches, and will provide opportunities for education, training, and public engagement. These broader impact activities include; 1) developing a course that would allow students to study multi-cellular interactions, 2) provide interdisciplinary training for the next generation of scientists, 3) allow for undergraduate internships for summer research experience, 4) create web-modules on the topic for citizen scientists, and 5) develop museum exhibits related to synthetic biology and cell-to-cell communication.This project aims to gain quantitative insight into how localized changes in a tissue propagate and impact tissue signaling and physiology. In particular, using an integrated experimental and computational approach, we will study how cAMP/PKA, Ca2+ and ERK signaling is coordinated within an individual epithelial cell, and how signals emanating from these pathway propagate from one cell to others in a tissue. Optogenetic tools will be developed to apply spatially and temporally precise perturbations to these pathways in designated single cells within a tissue, and then measure the resulting signaling and transcriptional activities in the sender cells where perturbations are initiated as well as receiver cells that sense the propagated perturbation. Emergent phenotypic repercussions of such perturbations, such as cellular mobility, will be assessed. To organize and interpret the data, generalize findings, and design maximally informed experiments, mathematical models that uniquely consider the tissue geometry and impact of spatial dimensions and heterogeneity on interactions within cell groups will be constructed. This multidisciplinary approach will allow for the generation of a quantitative understanding of the fundamental principles of collaboration in cell communities and the modalities by which local perturbations propagate and impact tissue physiology. This project is funded by the Systems and Synthetic Biology Program in the Division of Molecular and Cellular Biosciences.