Role of the Nlrp3 Inflammasome in Adaptive Immunity

说明(申请人提供)：铝佐剂，通常被称为“明矾”，是全世界人类和动物疫苗中最常用的佐剂。我们最近发现，明矾激活了一种名为Nlrp3炎症小体的细胞内天然免疫反应系统。然而，目前还不清楚炎性小体激活如何调节持久的获得性免疫。我们推测明矾可以激活抗原提呈细胞中的Nlrp3炎症体，导致IL-1家族成员的释放，从而为淋巴细胞的激活提供必要的启动信号。[使用Nlrp3，条件性caspase-1，IL-1RI和其他基因敲除小鼠，体外和体内研究将测试这一假说的组成部分，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的适应性免疫反应的细胞；2)定义明矾诱导的Nlrp3炎症小体激活控制T和B细胞启动的免疫调节产品。通过了解明矾如何通过这一先天途径协调有效的适应性免疫反应，我们将能够开发新一代的佐剂，专门针对免疫系统的适当组件，从而产生更有效的疫苗。]候选人：斯蒂芬妮·艾森巴特是免疫学和临床病理学/实验室医学方面的医学博士和博士，她计划解决有关疫苗佐剂作用机制的问题，目的是改进佐剂设计。她的长期职业目标是在一家学术机构获得一个终身教职的职位，她的大部分时间都致力于基础科学研究，辅之以参与病理部门的临床工作。为此，她选择了两位在有效培训年轻科学家方面有着悠久历史的导师，他们是耶鲁大学免疫生物学系的理查德·弗拉维尔博士和马克·什洛姆奇克博士。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。她还成立了一个职业咨询委员会，规划了实验室医学部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领域。因此，这项建议将解决我们对疫苗免疫学理解中至关重要的问题，并将为候选人作为独立内科科学家解决其他问题做好准备。 简介：针对传染性病原体的疫苗的开发一直是并将继续是全球卫生领域最重要的医疗干预措施之一。这一建议描述了必要的实验，以了解Nlrp3炎症体是免疫系统固有分支的一种成分，在氢氧化铝佐剂接种期间如何调节免疫。这样的理解可以促进新一代疫苗佐剂的开发。

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.