Collaborative Research: The Dynamics of the Innate Immune Systems: A Study of the Toll-like Receptors (TLR) Network

合作研究：先天免疫系统的动力学：Toll 样受体 (TLR) 网络的研究

• 批准号: 1137900
• 负责人: Calin Belta
• 金额: $ 14.25万
• 依托单位: Trustees of Boston University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1137900&HistoricalAwards=false
• 关键词: Collaborative; Research; Dynamics; Innate; Immune

Intellectual Merit: The first line of defense to microbial infections or tissue damage is the innate immune system, which responds to harmful stimuli by triggering inflammation, a defensive response that is essential for tissue repair and pathogen removal. However, excessive inflammation is harmful because it can produce further tissue damage; inflammation must therefore be countered by anti-inflammatory responses. Hence, it is crucial to understand how the dynamics of the pro- and anti-inflammatory responses of the immune system are regulated. The overarching aim of this project is to elucidate the regulation dynamics of the Toll-like family of receptors (TLR), which are components of the innate immune system that recognize microbial pathogens. The project constitutes a pilot study exploring the use of systems and control theory and formal methods to study the dynamics of the innate immune system. Formal methods is a branch of mathematics and theoretical computer science that has been developed to verify the execution of complex engineering systems. The investigators will use existing published experimental data from TLR excitation experiments, to develop an integrated mathematical model combining the dynamics of signaling and transcription networks. Further, they will develop novel formal methods to analyze this model. Because of the anticipated complexity of the TLR network, the investigators will initially test their framework using data generated in silico, as well as existing, smaller data sets from other signaling networks, such as the NF-kB network. It is anticipated that successful completion of this project will create a framework capable of producing testable predictions that can be used in subsequent studies of the TLR. Broader Impacts: While the project focuses on quantitative study of the dynamical properties of the TLR network, the theory that will be developed is expected to be broadly applicable to other phenomena related to the innate immunity, including, autoimmunity, chronic inflammation, and obesity. Furthermore, because of its generality, the framework developed in this project should lend itself to the study of other cellular signaling mechanisms and the related transcriptional regulation systems, for example, the growth-factor signaling system and the cell-cycle regulatory system. As part of this project, graduate and undergraduate students will be trained and prepared for academic and industrial careers at the leading edge of the interface between biology and engineering. The investigators will integrate the research activity into graduate and undergraduate curriculum. Outreach activities to K-12 students and teachers, particularly targeting students from underrepresented minorities, will be carried out under the auspices of BU Academy at Boston University and the Center for Initiatives in Pre-College Education (CIPCE) at Rensselaer.

智力优势：防御微生物感染或组织损伤的第一道防线是先天免疫系统，它通过触发炎症对有害刺激做出反应，这是一种对组织修复和病原体清除至关重要的防御反应。然而，过度的炎症是有害的，因为它会产生进一步的组织损伤;因此，炎症必须通过抗炎反应来对抗。因此，了解免疫系统的促炎和抗炎反应的动力学是如何调节的至关重要。该项目的首要目标是阐明Toll样受体家族（TLR）的调控动力学，TLR是识别微生物病原体的先天免疫系统的组成部分。该项目是一项试点研究，探索使用系统和控制理论和正式的方法来研究先天免疫系统的动态。形式化方法是数学和理论计算机科学的一个分支，它被开发用于验证复杂工程系统的执行。研究人员将利用TLR激发实验中现有的已发表实验数据，开发一个结合信号传导和转录网络动力学的综合数学模型。此外，他们将开发新的形式化方法来分析这个模型。由于TLR网络的预期复杂性，研究人员最初将使用计算机生成的数据以及来自其他信令网络（如NF-kB网络）的现有较小数据集来测试他们的框架。预计该项目的成功完成将创建一个框架，能够产生可测试的预测，可用于TLR的后续研究。更广泛的影响：虽然该项目侧重于TLR网络动力学特性的定量研究，但预计将开发的理论将广泛适用于与先天免疫相关的其他现象，包括自身免疫，慢性炎症和肥胖。此外，由于其通用性，本项目开发的框架应有助于研究其他细胞信号机制和相关转录调节系统，例如生长因子信号系统和细胞周期调节系统。作为该项目的一部分，研究生和本科生将接受培训，并为生物学和工程学之间接口的前沿学术和工业职业做好准备。研究人员将把研究活动纳入研究生和本科生课程。对K-12学生和教师的外联活动，特别是针对来自代表性不足的少数民族的学生，将在波士顿大学BU学院和伦斯勒大学预科教育倡议中心（CIPCE）的主持下进行。