The award, funded by the Systems and Synthetic Biology Program in MCB and the Biotechnology, Biochemical and Biomass Engineering Program in CBET, is to study how the response of an animal to noxious environmental conditions is coordinated across the cells and tissues of its body. The PI will use a combination of experimental and computational approaches to study the response of a model animal (a nematode) to elevated temperatures, an ancient mechanism present in all kingdoms of life. Novel experimental tools developed by the PI will be used to discriminate autonomous responses of individual cells from response that is coordinated among cells or throughout the organism. These data will be integrated into a computational model aimed to identify mechanisms used to guarantee a consistent response. A central goal of this project is to develop a conceptual framework for studying distributed biological systems, essential for adaptation of an organism to changing environment and for combating disease and cancer. To increase awareness to inter-disciplinary research, the PI will form a virtual network of high-school students and teachers who will take part in the research program. Emphasis will be given to recruitment of teams from schools in disadvantaged areas. Participants in the project will learn key concepts in genetics, statistics and physics, and will gain personal experience in inter-disciplinary research.

The heat-shock response is a highly conserved molecular response to environmental conditions that disrupt protein homeostasis. Its major role is to prevent protein misfolding and aggregation, both under normal conditions and under stress. In a multi-cellular organism this is a major challenge, as the proteome of different cells can be markedly different. Heat-shock response therefore provides an opportunity to address a fundamental question about signals and regulation in a multi-cellular organism: how the regulatory network controls a coordinated response, while allowing different levels of activation that fit the needs of specific cells. In this project the PI will test the hypothesis that an integration of systemic and local signals drives the activation dynamics of Heat-shock factor 1 (HSF-1), a highly conserved central regulator of heat-shock response. Multiple signals converge to regulate the activity of HSF-1. Some signals convey local information about the status of the proteome in the cell, while others are transmitted from other cells and neurons. To shed light on the distribution of signals that drive the dynamics of HSF-1, the PI will measure dynamical and stochastic correlations between cells during heat-shock response. Careful quantitative characterization of the response of HSF-1 and its downstream targets to local and external signals will be conducted using transgenic strains in a unique microfluidic-based setup developed by the PI. The acquired data will drive the development of a spatially extended computational model to predict systemic and local aspects of the regulatory network. The computational model is will be used to identify inter-cellular interactions and make predictions about their functional roles. These predictions will be tested experimentally. In light of this model, the PI will characterize the embryonic and post-embryonic development of the heat-shock response network.

National Science Foundation (NSF)
Division of Molecular and Cellular Biosciences (MCB)
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David Rockcliffe
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Harvard University
United States
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