权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

NSF/MCB-BSF: Quantitative analysis and modeling of Notch signaling using in vivo synthetic biology

NSF/MCB-BSF：利用体内合成生物学对 Notch 信号传导进行定量分析和建模

基本信息

批准号：
1715822
负责人：
Brian Gebelein
金额：
$ 85万
依托单位：
Children's Hospital Medical Center
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：
2017-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1715822&HistoricalAwards=false
关键词：
NSF MCB BSF Quantitative analysis

项目摘要

How an animal develops complex tissue types during its lifetime is an important and fundamental question. Many cell signals are required to work together so this process works flawlessly. This project will systematically build a theoretical understanding of a cell signaling pathway in developing fruit fly embryos. Like many genetic pathways required for animal development, this signaling pathway was initially discovered using fruit flies and later shown to be essential for normal human development and health. This project will foster scientific collaborations between the U.S and Israel. Students from biology, engineering, and physics will examine how an external signal is converted into specific outputs using experimental and computational approaches. Both graduate and undergraduate students will be trained by a multidisciplinary research team that has wide-ranging expertise in laboratory and theoretical methods. Undergraduate students in Biomedical and Computer engineering will gain hands-on laboratory experiences and work with advanced students as a team, to achieve a common goal. This will help them to communicate ideas and results to fellow students and will promote interdisciplinary training.The central aim of this collaborative research project is to understand how different cell types convert the same cell signaling pathway into distinct responses during animal development. Defining how a signal invokes appropriate cell responses is of fundamental importance because signaling pathways ensure essential cell types are generated throughout an organism's lifespan. The Notch signaling pathway in Drosophila is iteratively used to invoke distinct responses in different cell types throughout animal development. The specific goals of this project are to develop a systematic, quantitative understanding of how the Notch signal is converted into cell-specific outputs using an in vivo synthetic biology approach and mathematical modeling. Drosophila carrying a set of reporters that systematically vary in number and architecture of Notch-regulated DNA binding sites will be created. Quantitative expression analysis and transcription factor occupancy data will be obtained using high resolution imaging of fixed and live tissues. Experimental data will be used to build mathematical models and computational simulations. Models will be based on a statistical mechanics description of transcription to describe how key parameters (DNA binding sites, ratios of effector proteins, binding affinities, and protein degradation) alter Notch output. Predictions from these models will be tested experimentally and will be used to improve the mathematical models. A quantitative description for the core Notch transcription module will provide a framework to systematically explore the role of additional biological factors on Notch-mediated transcription.This collaborative US/Israel project is supported by the US National Science Foundation and the Israeli Binational Science Foundation.

动物在其一生中如何发育复杂的组织类型是一个重要而基本的问题。许多细胞信号需要一起工作，所以这个过程是无障碍的。该项目将系统地建立对果蝇胚胎发育中细胞信号通路的理论理解。与动物发育所需的许多遗传途径一样，这种信号通路最初是在果蝇中发现的，后来被证明对人类正常发育和健康至关重要。该项目将促进美国和以色列之间的科学合作。来自生物学，工程学和物理学的学生将研究如何使用实验和计算方法将外部信号转换为特定输出。研究生和本科生都将接受多学科研究团队的培训，该团队在实验室和理论方法方面具有广泛的专业知识。生物医学和计算机工程专业的本科生将获得实践实验室经验，并与先进的学生作为一个团队合作，以实现共同的目标。这将有助于他们与同学交流想法和结果，并将促进跨学科的培训。这个合作研究项目的中心目标是了解不同类型的细胞如何在动物发育过程中将相同的细胞信号通路转化为不同的反应。确定信号如何引起适当的细胞反应是至关重要的，因为信号通路确保在生物体的整个生命周期中产生必要的细胞类型。果蝇中的Notch信号通路在整个动物发育过程中反复用于在不同细胞类型中引起不同的反应。该项目的具体目标是使用体内合成生物学方法和数学建模，对Notch信号如何转化为细胞特异性输出进行系统的定量理解。将创建携带一组在Notch调节的DNA结合位点的数量和结构上系统地变化的报告基因的果蝇。将使用固定和活组织的高分辨率成像获得定量表达分析和转录因子占用数据。实验数据将用于建立数学模型和计算模拟。模型将基于转录的统计力学描述来描述关键参数（DNA结合位点、效应蛋白的比率、结合亲和力和蛋白质降解）如何改变Notch输出。这些模型的预测将通过实验进行测试，并将用于改进数学模型。对Notch核心转录模块的定量描述将为系统地探索其他生物因子对Notch介导的转录的作用提供一个框架。