Immune Response Consortium: Integrated In Silico, In Vitro, and In Vivo Studies

免疫反应联盟：集成计算机模拟、体外和体内研究

• 批准号: 7894721
• 负责人: Arup K. Chakraborty
• 金额: $ 164.75万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7894721
• 关键词: Immune; Response; Consortium; Integrated; Silico

DESCRIPTION (provided by applicant): The global burden of disease caused by intracellular pathogens remains one of the great challenges facing the biomedical community. Such pathogens and their engineered variants could also be employed in acts of bioterrorism. The innate and adaptive components of the immune system enable organisms to target and eliminate pathogens or cells infected with them. Activation of the adaptive immune response to intracellular pathogens is orchestrated by T cells. A central hypothesis of this program project is that understanding how T cells detect antigen with extraordinary sensitivity and how T cell activation is regulated is a key for developing rational protocols for combating infections, autoimmune disorders, and bioterrorism agents. In particular, this knowledge should lead to the development of vaccines and novel forms of therapeutics to treat potentially deadly infections. Developing an integrated mechanistic understanding of the various processes involved in T cell activation presents formidable challenges. One challenge is that T cell activation involves processes that occur over a wide spectrum of length and time scales ranging from molecular recognition events (that occur on millisecond time scales) to proliferation of specific T cell clones in response to infection (which happens after several days). A second challenge is that each of these processes is the result of collective dynamic events involving many molecular and/or cellular components, and it is difficult to intuit mechanistic understanding by examining only a few experimental reporters. The purpose of this program project is to bring together a team of scientists (the Immune Response Consortium) who are committed to developing an integrated understanding of the multiscale processes pertinent to T cell activation in response to a real pathogen. We will pursue this goal by building on a new paradigm where all members of the team will work on different aspects of the same biological process using methods that bring together the physical and life sciences. Computational studies (rooted in the physical sciences) will be seamlessly integrated with in vitro and in vivo genetic and biochemical experiments to understand the adaptive immune response to the NIH Category B pathogen, Listeria monocytogenes.

描述（由申请人提供）：由细胞内病原体引起的全球疾病负担仍然是生物医学界面临的巨大挑战之一。此类病原体及其工程变体也可用于生物恐怖主义行为。免疫系统的先天和适应性成分使生物体能够瞄准并消除病原体或感染它们的细胞。对细胞内病原体的适应性免疫反应的激活是由 T 细胞协调的。该项目的一个中心假设是，了解 T 细胞如何以非凡的灵敏度检测抗原以及如何调节 T 细胞激活是制定对抗感染、自身免疫性疾病和生物恐怖主义制剂的合理方案的关键。特别是，这些知识应该会导致疫苗和新疗法的开发，以治疗潜在的致命感染。对 T 细胞激活所涉及的各种过程建立一个综合的机制理解提出了巨大的挑战。一个挑战是，T 细胞激活涉及在广泛的长度和时间尺度上发生的过程，从分子识别事件（发生在毫秒时间尺度）到特定 T 细胞克隆响应感染的增殖（发生在几天后）。第二个挑战是，每个过程都是涉及许多分子和/或细胞成分的集体动态事件的结果，并且仅通过检查少数实验报告基因很难直观地理解机制。该计划项目的目的是汇集一个科学家团队（免疫反应联盟），他们致力于对与真实病原体反应的 T 细胞激活相关的多尺度过程进行综合理解。我们将通过建立一个新的范式来实现这一目标，在该范式中，团队的所有成员都将使用将物理和生命科学结合在一起的方法来研究同一生物过程的不同方面。计算研究（植根于物理科学）将与体外和体内遗传和生化实验无缝集成，以了解对 NIH B 类病原体单核细胞增生李斯特氏菌的适应性免疫反应。

项目成果

Sensitivity of T cells to antigen and antagonism emerges from differential regulation of the same molecular signaling module.

T 细胞对抗原和拮抗的敏感性源于同一分子信号传导模块的差异调节。

• DOI: 10.1073/pnas.0611482104
• 发表时间: 2007
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Wylie,DennisC;Das,Jayajit;Chakraborty,ArupK
• 通讯作者: Chakraborty,ArupK

Regulation of signal duration and the statistical dynamics of kinase activation by scaffold proteins.

• DOI: 10.1371/journal.pcbi.1000099
• 发表时间: 2008-06-27
• 期刊: PLoS computational biology
• 影响因子: 4.3
• 作者: Locasale JW;Chakraborty AK
• 通讯作者: Chakraborty AK

Maximum entropy reconstructions of dynamic signaling networks from quantitative proteomics data.

• DOI: 10.1371/journal.pone.0006522
• 发表时间: 2009-08-26
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Locasale JW;Wolf-Yadlin A
• 通讯作者: Wolf-Yadlin A

Three-state kinetic mechanism for scaffold-mediated signal transduction.

支架介导的信号转导的三态动力学机制。

• DOI: 10.1103/physreve.78.051921
• 发表时间: 2008
• 期刊: Physical review. E, Statistical, nonlinear, and soft matter physics
• 作者: Locasale,JasonW

Efficient stochastic simulation of reaction-diffusion processes via direct compilation.

• DOI: 10.1093/bioinformatics/btp387
• 发表时间: 2009-09-01
• 期刊: Bioinformatics (Oxford, England)
• 作者: Lis M;Artyomov MN;Devadas S;Chakraborty AK
• 通讯作者: Chakraborty AK