Role of the Nlrp3 Inflammasome in Adaptive Immunity

Nlrp3 炎症小体在适应性免疫中的作用

• 批准号: 8081119
• 负责人: Stephanie Caroline Eisenbarth
• 金额: $ 13.35万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8081119
• 关键词: Address; Adenovirus Vector; Adjuvant; Adjuvant Study; Advisory Committees; Affect; Aluminum; Aluminum Hydroxide; Animals; Antibodies; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Biomedical Research; Bone Marrow; CD4 Positive T Lymphocytes; Caspase-1; Cell physiology; Cells; Chimera organism; Chitosan; Clinical; Clinical Pathology; Clinical Trials; Complement; Critical Pathways; Cytokine Receptors; Dendritic Cells; Development; Doctor of Philosophy; Family; Family member; Generations; Genes; Genetic; Genomics; Goals; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunobiology; Immunology; In Vitro; Inflammatory; Institution; Interleukin-1; Interleukin-18; Intervention; Investigation; Knockout Mice; Knowledge; Laboratories; Licensing; Light; Listeria monocytogenes hlyA protein; Lymphocyte Activation; Medical; Medicine; Mentors; Methodology; Modeling; Molecular; Morbidity - disease rate; Mus; Pathology; Pathway interactions; Pattern recognition receptor; Phagocytosis; Physicians; Play; Population; Positioning Attribute; Preparation; Proteins; Quil A; Recording of previous events; Research; Research Project Grants; Resources; Role; Scientist; Screening procedure; Signal Transduction; Stimulus; System; T-Cell Receptor; T-Lymphocyte; Testing; Time; Training; United States; Universities; Uric Acid; Vaccination; Vaccine Adjuvant; Vaccines; adaptive immunity; aluminum sulfate; base; career; cell type; cytokine; design; global health; improved; in vivo; macrophage; medical schools; member; microbial; nanoparticle; pathogen; receptor; research study; response; vaccine development

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.

描述（由申请方提供）：铝佐剂，通常称为“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称为Nlrp 3炎性体的细胞内先天免疫应答系统。然而，尚不清楚炎性小体激活如何调节持久的适应性免疫。我们假设明矾触发抗原呈递细胞中的Nlrp 3炎性小体活化，导致IL-1家族成员的释放，其为淋巴细胞活化提供必要的引发信号。[使用Nlrp 3、条件性半胱天冬酶-1、IL-1 RI和其他敲除小鼠系，体外和体内研究将测试该假设的组成部分，具体目的如下：1）鉴定通过Nlrp 3炎性体控制对氢氧化铝佐剂的适应性免疫应答的细胞，和2）定义明矾的免疫调节产物。诱导控制T和B细胞引发的Nlrp 3炎性体活化。通过了解明矾通过这种先天途径协调有效的适应性免疫反应的方式，我们将能够开发新一代佐剂，以特异性靶向免疫系统的适当成分，从而产生更有效的疫苗。候选人：Stephanie Eisenbarth是一名医学博士，在免疫学和临床病理学/实验室医学方面接受过培训，她计划解决有关疫苗佐剂作用机制的问题，旨在改进佐剂设计。她的长期职业目标是在学术机构获得终身职位，她的大部分时间都用于基础科学研究，并辅之以病理学部门的临床参与。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，耶鲁大学免疫生物学系的Richard Flavell博士和Mark Shlomchik博士。耶鲁大学医学院的生物医学研究中心将提供充足的科学和临床资源来进行上述研究。她还建立了一个职业咨询委员会，计划在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，该项目将通过解决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的医生-科学家出现的其他问题。 叙述：针对传染性病原体的疫苗的开发一直是并将继续是全球健康中最重要的医学干预措施之一。该提议描述了理解Nlrp 3炎性体（免疫系统的先天分支的组分）如何在用氢氧化铝佐剂接种期间调节免疫所必需的实验。这种理解可以促进新一代疫苗佐剂的开发。