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NSF-ANR: Precision of collective, distributed, dynamic gene regulation

NSF-ANR：集体、分布式、动态基因调控的精确性

基本信息

批准号：
2209996
负责人：
Ilya Nemenman
金额：
$ 40.41万
依托单位：
Emory University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2209996&HistoricalAwards=false
关键词：
NSF ANR Precision collective distributed

项目摘要

All multicellular organisms, including humans, develop from a single cell by engaging a network of genes that activate and suppress each other in a concerted program, providing different cells with distinct, precise molecular identities. The rules of this program are only now beginning to be understood. Specifically, characterizing biophysical mechanisms that biology employs to make development robust to the inevitable randomness in molecular interactions remains a frontier question in modern developmental biology. In this project, a team of U.S. and French researchers will explore, using theoretical physics methods and computer simulations, effects of many so called “enhancers” – regions on the DNA that some genes can use to regulate others – on the precision of organism development. The team will use the fruit fly as a model organism. Understanding these effects will extend our basic scientific knowledge, and it may in the future impact human health since many diseases trace their roots to abnormalities in developmental genetic networks. The broader impacts will include training of the next generation of the workforce at the interface of physics and biology – in the participating research groups and through an international summer school organized by these groups.The focus is on building theoretical and computational models to understand the physical limits imposed by molecular architectures of gene regulatory systems on the precision and speed of regulation. The project will develop a predictive analytical and computational theory of the role of dynamical, spatially extended interactions among multiple enhancers, multiple transcription factors, and multiple promoters on precise gene regulation in eukaryotic development. Early fruit fly development will be used as an example, motivated by large amounts of existing data and the theoretical teams’ existing relationship with experimentalists. The theory will address the role of multiple proximal and distal enhancers, characterize the effects of crosstalk among various enhancers, promoters, and transcription factors on precision of gene regulation, and elucidate the constraints that the dynamical nature of the development process imposes on molecular implementations of transcriptional hubs.This collaborative US/France project is supported by the US National Science Foundation and the French Agence Nationale de la Recherche, where NSF funds the US investigator and ANR funds the partners in France.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

所有的多细胞生物，包括人类，都是从一个单细胞发展而来的，通过一个协调一致的程序来激活和抑制彼此的基因网络，为不同的细胞提供不同的，精确的分子身份。这个程序的规则现在才开始被理解。具体来说，表征生物学用来使发育对分子相互作用中不可避免的随机性具有鲁棒性的生物物理机制仍然是现代发育生物学的前沿问题。在这个项目中，一个由美国和法国研究人员组成的团队将利用理论物理方法和计算机模拟，探索许多所谓的“增强子”--DNA上一些基因可以用来调节其他基因的区域--对生物体发育精度的影响。该研究小组将使用果蝇作为模式生物。了解这些影响将扩展我们的基本科学知识，它可能在未来影响人类健康，因为许多疾病的根源都可以追溯到发育遗传网络的异常。更广泛的影响将包括在物理学和生物学的界面上培训下一代劳动力-在参与的研究小组中，并通过这些小组组织的国际暑期学校，重点是建立理论和计算模型，以了解基因调控系统的分子结构对调控精度和速度施加的物理限制。该项目将开发一个预测分析和计算理论的作用，多个增强子，多个转录因子和多个启动子之间的动态，空间扩展的相互作用在真核发育中的精确基因调控。早期果蝇的发展将被用作一个例子，大量的现有数据和理论团队与实验人员的现有关系的动机。该理论将解决多个近端和远端增强子的作用，表征各种增强子，启动子和转录因子之间的串扰对基因调控精度的影响，并阐明了发展过程的动态性质对转录枢纽分子实现的限制。法国项目得到了美国国家科学基金会和法国国家研究机构的支持，其中NSF资助美国调查员，ANR资助法国的合作伙伴。该奖项反映了NSF的法定使命，并通过使用基金会的学术价值和更广泛的影响审查标准。