The Distributed Regulatory Network that Integrates Local and Systemic Signals to Regulate Heat Shock Response

集成局部和系统信号来调节热冲击反应的分布式调节网络

• 批准号: 1413134
• 负责人: Erel Levine
• 金额: $ 74.27万
• 依托单位: Harvard University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1413134&HistoricalAwards=false
• 关键词: Distributed; Regulatory; Network; Integrates; Local

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.

该奖项由MCB的系统与合成生物学项目和CBET的生物技术、生物化学和生物质工程项目资助，旨在研究动物对有害环境条件的反应如何在其身体的细胞和组织中协调。PI将使用实验和计算方法相结合的方法来研究模型动物（线虫）对高温的反应，这是一种存在于所有生命王国中的古老机制。PI开发的新实验工具将用于区分单个细胞的自主反应与细胞之间或整个生物体的协调反应。这些数据将被整合到一个计算模型中，旨在确定用于保证一致反应的机制。该项目的一个中心目标是为研究分布式生物系统制定一个概念框架，这对于生物体适应不断变化的环境以及防治疾病和癌症至关重要。为了提高对跨学科研究的认识，PI将建立一个虚拟的高中学生和教师网络，他们将参加研究计划。重点将放在从贫困地区的学校招募团队。该项目的参与者将学习遗传学，统计学和物理学的关键概念，并将获得跨学科研究的个人经验。热休克反应是一种高度保守的分子对破坏蛋白质稳态的环境条件的反应。它的主要作用是防止蛋白质在正常条件下和压力下的错误折叠和聚集。在多细胞生物体中，这是一个重大挑战，因为不同细胞的蛋白质组可能明显不同。因此，热休克反应提供了一个机会来解决一个关于多细胞生物体中信号和调节的基本问题：调节网络如何控制协调反应，同时允许不同水平的激活以满足特定细胞的需要。在这个项目中，PI将测试系统和局部信号的整合驱动热休克因子1（HSF-1）的激活动力学的假设，HSF-1是一种高度保守的热休克反应的中枢调节因子。多个信号会聚以调节HSF-1的活性。一些信号传递关于细胞中蛋白质组状态的局部信息，而另一些信号则从其他细胞和神经元传递。 为了阐明驱动HSF-1动力学的信号分布，PI将测量热休克反应期间细胞之间的动态和随机相关性。HSF-1及其下游靶标对局部和外部信号的响应的仔细定量表征将在PI开发的独特的基于微流体的设置中使用转基因菌株进行。所获得的数据将推动空间扩展计算模型的开发，以预测监管网络的系统和局部方面。计算模型将用于识别细胞间的相互作用，并预测它们的功能作用。这些预测将在实验中得到检验。根据该模型，PI将表征热休克反应网络的胚胎和胚胎后发育。