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Unraveling the propagation and repercussions of localized perturbations within tissues

揭示组织内局部扰动的传播和影响

基本信息

批准号：
1715108
负责人：
Hana El-Samad
金额：
$ 80万
依托单位：
University of California-San Francisco
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1715108&HistoricalAwards=false
关键词：
Unraveling propagation repercussions localized perturbations

项目摘要

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.

这项计划的目标是揭示重要的信号是如何在上皮组织中的细胞之间传播的，上皮组织形成了大多数动物器官的衬里。这种沟通对于维持健康的组织，伤口愈合以及应对感染和癌症至关重要。该项目将采用实验和建模方法的多学科组合，并将提供教育，培训和公众参与的机会。这些更广泛的影响活动包括：1）开发一门课程，使学生能够研究多细胞相互作用，2）为下一代科学家提供跨学科培训，3）允许本科生实习夏季研究经验，4）为公民科学家创建主题的网络模块，以及5）发展与合成生物学和细胞间通讯相关的博物馆展品。该项目旨在定量了解组织中的局部变化如何传播和影响组织信号和生理。特别是，使用一个综合的实验和计算方法，我们将研究cAMP/PKA，Ca 2+和ERK信号是如何协调在一个单独的上皮细胞，以及如何从这些途径发出的信号传播从一个细胞到其他组织。将开发光遗传学工具，以在组织内指定的单细胞中对这些通路施加空间和时间上精确的扰动，然后测量扰动启动的发送细胞以及感测传播扰动的接收细胞中产生的信号传导和转录活动。将评估此类扰动的紧急表型影响，如细胞移动性。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，该模型唯一考虑组织几何形状以及空间维度和异质性对细胞组内相互作用的影响。这种多学科方法将使人们能够定量了解细胞群落协作的基本原则以及局部扰动传播和影响组织生理学的方式。该项目由分子和细胞生物科学部的系统和合成生物学计划资助。