New Costimulatory Pathways: Functions and Interactions

新的共刺激途径：功能和相互作用

• 批准号: 6873684
• 负责人: Arlene H. Sharpe
• 金额: $ 190.49万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6873684
• 关键词: T lymphocyte; biological signal transduction; clinical research; leukocyte activation /transformation; surface antigens

DESCRIPTION (provided by applicant): This Costimulation PPG grant is driven by the fundamental and therapeutic importance of T cell costimulation for regulating T cell activation and tolerance. The growing number of T cell costimulatory pathways together with the dynamic nature of the immune response suggests that there may be a functional hierarchy of costimulatory molecules for regulating responses of nave, effector, and memory T cells. Understanding the functions of T cell costimulatory pathways in specific disease models should enable manipulation of costimulatory signals to promote T cell activation or T cell tolerance for therapeutic purposes. The major objectives of the Costimulation PPG is to develop an understanding of the roles of T cell costimulatory pathways in regulating T cell activation and tolerance in defined experimental models of transplantation, autoimmunity, allergy/asthma, and infections. We will address the following questions: 1. Are T cell costimulatory pathways merely redundant or do they provide distinct and unique functions in different types of immune responses? 2. What are the important and unique interactions between the various pathways? 3. What are the effects and mechanisms of targeting of these pathways in vivo? Other objectives include fostering interactions between experts in the field, developing novel tools (animals and reagents) to share among investigators, and building a network of collaborations to share ideas, models and reagents. We plan to achieve these objectives by: 1. identifying, targeting and studying the functions of new costimulatory pathways in well defined experimental models in vivo; 2) analyzing the interactions among the new, and with the well characterized T cell costimulatory pathways in these models. We are proposing 4 Projects (Transplantation, Autoimmunity, Allergy/Asthma, Infections) and 4 Cores (Administrative, Molecular/Signaling, Transgenic/Knockout, Biophysical Characterization). The Administrative Core will be responsible for providing scientific direction and coordination, fiscal oversight and administrative support for the PPG among 7 institutions in 5 different cities. This PPG should provide fundamental knowledge for developing novel translational research opportunities aimed at inducing T cell tolerance to prevent transplant rejection and ameliorate autoimmune and allergic diseases, as well as developing more effective immunity to microbes.

描述（由申请人提供）：该共刺激PPG资助是由T细胞共刺激对调节T细胞活化和耐受的基本和治疗重要性驱动的。T细胞共刺激通路数量的增加以及免疫应答的动态性质表明，可能存在一个共刺激分子的功能层次，用于调节免疫应答。ve、效应T细胞和记忆T细胞。理解T细胞共刺激通路在特定疾病模型中的功能应该能够操纵共刺激信号以促进T细胞活化或T细胞耐受用于治疗目的。共刺激PPG的主要目的是了解T细胞共刺激通路在移植、自身免疫、过敏/哮喘和感染的定义实验模型中调节T细胞活化和耐受的作用。我们将解决以下问题：1. T细胞共刺激通路仅仅是多余的，还是它们在不同类型的免疫应答中提供了不同的独特功能？2.各种途径之间有哪些重要而独特的相互作用？3.体内靶向这些通路的作用和机制是什么？其他目标包括促进该领域专家之间的互动，开发新的工具（动物和试剂）以供研究人员共享，并建立一个合作网络以共享想法，模型和试剂。我们计划通过以下方式实现这些目标：1.在明确的体内实验模型中鉴定、靶向和研究新的共刺激途径的功能; 2）分析这些模型中新的T细胞共刺激途径之间的相互作用以及与充分表征的T细胞共刺激途径的相互作用。我们提出了4个项目（移植，自身免疫，过敏/哮喘，感染）和4个核心（管理，分子/信号，转基因/敲除，生物物理表征）。行政核心将负责为PPG在5个不同城市的7个机构之间提供科学指导和协调、财政监督和行政支持。这个PPG应该为开发新的转化研究机会提供基础知识，旨在诱导T细胞耐受性，以防止移植排斥反应，改善自身免疫性和过敏性疾病，以及开发更有效的微生物免疫力。