Role of the Nlrp3 Inflammasome in Adaptive Immunity

描述（由申请人提供）：铝佐剂，通常称为“明矾”，是世界范围内人类和动物疫苗中最常用的佐剂。我们最近发现明矾激活细胞内先天免疫反应系统称为Nlrp3炎性体。然而，炎性体活化如何调节长期适应性免疫仍不清楚。我们假设明矾触发抗原呈递细胞中的Nlrp3炎性体激活，导致IL-1家族成员的释放，这为淋巴细胞激活提供了必要的启动信号。[使用Nlrp3、条件caspase-1、IL-1RI和其他敲除小鼠系，体外和体内研究将测试这一假设的组成部分，具体目的如下：1)确定通过Nlrp3炎症小体控制对氢氧化铝佐剂适应性免疫反应的细胞；2)确定铝诱导的Nlrp3炎症小体激活控制T和B细胞启动的免疫调节产物。]通过了解明矾如何通过这种先天途径协调有效的适应性免疫反应，我们将能够开发出新一代的佐剂，专门针对免疫系统的适当成分，从而产生更有效的疫苗。候选人：Stephanie Eisenbarth，医学博士，免疫学和临床病理学/实验室医学博士，她计划解决有关疫苗佐剂作用机制的问题，目的是改进佐剂的设计。她的长期职业目标是在学术机构获得终身职位，大部分时间致力于基础科学研究，并在病理学部门参与临床工作。为此，她选择了耶鲁大学免疫生物学系的Richard Flavell博士和Mark Shlomchik博士作为导师，他们在培养年轻科学家方面有着悠久的历史。耶鲁大学医学院的生物医学研究中心将为开展上述研究提供充足的科学和临床资源。她还建立了一个职业咨询委员会，规划了实验室医学系正在进行的临床活动，并概述了一个为期5年的研究项目，该项目将通过处理新的调查和方法来扩大她在免疫学领域的专业知识。因此，该提案将解决我们对疫苗免疫学的理解中至关重要的问题，并将使候选人准备好处理作为独立医生科学家出现的其他问题。

DESCRIPTION (provided by applicant): Aluminum adjuvants, typically referred to as "alum", are the most commonly used adjuvants in human and animal vaccines worldwide. We recently discovered that alum activates an intracellular innate immune response system called the Nlrp3 inflammasome. However, it remains unclear how inflammasome activation regulates long-lasting adaptive immunity. We hypothesize that alum triggers Nlrp3 inflammasome activation in antigen presenting cells, resulting in the release of IL-1 family members, which provide requisite priming signals for lymphocyte activation. [Using Nlrp3, conditional caspase-1, IL-1RI and other knockout mouse lines, both in vitro and in vivo studies will test the components of this hypothesis with the following specific aims: 1) Identify the cells that control the adaptive immune response to aluminum hydroxide adjuvants via the Nlrp3 inflammasome and 2) Define the immunoregulatory products of alum-induced Nlrp3 inflammasome activation that control T and B cell priming. By understanding the way in which alum orchestrates an effective adaptive immune response through this innate pathway, we will be able to develop new generations of adjuvants to specifically target the appropriate components of the immune system, resulting in more effective vaccines.] Candidate: Stephanie Eisenbarth is an MD, PhD trained in immunology and clinical pathology/laboratory medicine and she plans to address questions regarding the mechanism of action of vaccine adjuvants with the aim of improving adjuvant design. Her long-term career goal is to obtain a tenure-track position at an academic institution with a majority of her time dedicated to basic scientific investigation, complemented with clinical involvement in a pathology department. To this end, she has chosen two mentors who have a long history of effectively training young scientists, Dr. Richard Flavell and Dr. Mark Shlomchik in the Department of Immunobiology at Yale University. The biomedical research center at Yale School of Medicine will provide ample scientific and clinical resources to pursue the research proposed above. She has also established a career advisory committee, planned on-going clinical activities in the Department of Laboratory Medicine and outlined a 5-year research project that will expand her field of expertise within immunology by tackling new lines of investigation and methodologies. Therefore this proposal will address critically important questions in our understanding of vaccine immunology and will prepare the candidate to approach additional questions that arise as an independent physician-scientist. Narrative: The development of vaccines against infectious pathogens has been and continues to be one of the most important medical interventions in global health. This proposal delineates the experiments necessary to understand how the Nlrp3 inflammasome, a component of the innate branch of the immune system, regulates immunity during vaccination with aluminum hydroxide adjuvants. Such an understanding could facilitate the development of a new generation of vaccine adjuvants.