The role of NALPs in innate immunity

描述（由申请人提供）：本提案描述了一个为期4年的传染病学术生涯发展培训计划。首席研究员在天普大学（Temple University）获得免疫学博士和医学博士学位，在耶鲁大学医学院（Yale University School of Medicine）接受内科住院医师培训，目前正在同一研究所完成传染病研究。该计划将允许候选人扩展他以前的科学技能，并成为先天免疫和宿主-病原体相互作用领域的精通。理查德·弗拉威尔博士将指导首席研究员的科学发展。Flavell博士是先天免疫领域公认的领导者。Flavell博士是免疫生物学部门的主席，并成功地培养了许多博士后研究员和研究生。研究将集中在一个新发现的细胞质分子家族，称为NALPs，它是形成促炎反应的关键因素。我们之前已经证明NALP3和ASC是caspase-1在多种炎症刺激下激活所必需的。我们计划研究NALP3/ASC/caspase-1通路是如何被调控的，并将使用功能缺失诱变来评估NALP10在这一过程中的生理作用。具体目的包括：1)确定NALP10是否可以抑制NALP3/ASC/caspase-1通路，并阐明这种抑制发生的机制。2)确定NALPS和IPAF如何指导caspase-1活性对细胞因子加工和/或细胞死亡的影响。3)检查NALPS在类风湿关节炎关节炎症的诱导中是否必要，以及NALP10是否可以抑制这一过程。了解NALP家族在先天免疫中的作用具有许多重要的健康相关意义，从对抗感染到理解炎症性疾病（如周期性发热综合征和类风湿性关节炎）背后的机制。此次K08奖将极大地帮助候选人在先天免疫和炎症方面的研究，并为他提供时间和资源，使他成为一名熟练的独立研究者。

DESCRIPTION (provided by applicant): This proposal describes a 4 year training program for the development of an academic career in Infectious Diseases. The principal investigator has completed an M.D. and a Ph.D. in Immunology at Temple University, residency training in Internal Medicine at Yale University School of Medicine and is currently completing an Infectious Diseases fellowship at the same institute. This program will allow the candidate to expand on his previous scientific skills and to become proficient in the fields of innate immunity and host-pathogen interactions. Dr. Richard Flavell will mentor the principal investigator's scientific development. Dr. Flavell is a recognized leader in the field of innate immunity. Dr. Flavell is the Chairman of the Section of Immunobiology, and has successfully trained numerous postdoctoral fellows and graduate students. Research will focus on a newly discovered family of cytoplasmic molecules called NALPs, which serve as key elements in the formation of proinflammatory responses. We have previously demonstrated that NALP3 and ASC are required for the activation of caspase-1 in response to multiple inflammatory stimuli. We plan to examine how the NALP3/ASC/caspase-1 pathway is regulated, and will use loss of function mutagenesis to evaluate the physiologic role of NALP10 in this process. The specific aims include: 1) Determining if NALP10 can inhibit the NALP3/ASC/caspase-1 pathway and elucidating the mechanism by which such an inhibition occurs. 2) Determining how NALPS and IPAF can direct the activity of caspase-1 towards cytokine processing and/or cell death. 3) Examining if NALPS is necessary for the induction of joint inflammation in rheumatoid arthritis and if NALP10 can inhibit this process. Understanding the role the NALP family plays in innate immunity has many important health-related implications, ranging from fighting infections to understanding the mechanisms behind inflammatory disorders such as the periodic fever syndromes and rheumatoid arthritis. This K08 award will greatly assist the candidate's research into innate immunity and inflammation, and provide him with time and resources to develop into a skilled independent investigator.