CRITICAL ROLE OF THE ASC/CASPASE-1 PATHWAY IN TICK-BORNE RICKETTSIOSES

描述（由申请人提供）：本提案描述了一个为期三年的监督职业发展计划，在公共卫生研究。Joap佩德拉博士在普渡大学完成了医学昆虫学博士课程，目前是耶鲁大学的“布朗-考克斯医学研究员”，在免疫生物学领域拓展了他的科学技能。佩德拉博士致力于成为蜱传立克次体病领域的独立研究者。蜱传立克次体病与疾病控制和预防中心定义的健康保护目标直接相关。蜱传立克次体病原体不仅有可能影响所有人群的健康，而且在恐怖袭击中还可被用作生物武器。Fikrig博士将指导佩德拉博士的科学发展。Fikrig博士是耶鲁大学医学、微生物发病机制和公共卫生教授，也是蜱传疾病领域公认的领导者。该研究将集中在对嗜吞噬细胞无形体和康氏立克次体的免疫机制，这两种病原体来自蜱传立克次体组。对A. phagocytophilum和R.康诺里人基本上是未知的。佩德拉博士的初步结果表明，Nod样受体在抗A.嗜吞噬细胞菌感染Nod样受体识别细胞内病原体，并通过其对蛋白酶caspase-1的作用触发细胞因子IL-1b和IL-18。本申请中描述的研究方案旨在（1）研究在A.（2）探讨caspase-1/IL-18在A.（3）鉴定在嗜吞噬细胞菌中激活caspase-1的Nod样受体。conorii感染。为了实现这些目标，佩德拉博士将免费使用耶鲁大学的现代设施，并将利用免疫生物学、微生物发病机理和蛋白质组学方面的最新技术。

DESCRIPTION (provided by applicant): This proposal describes a three year supervised career development program in Public Health research. Joap Pedra, Ph.D. completed his doctoral program in Medical Entomology at Purdue University and is currently a "Brown-Coxe Fellow of Medicine" at Yale University expanding his scientific skills in the field of immunobiology. Dr. Pedra is committed towards becoming an independent investigator in the field of tick-borne rickettsioses. Tick-borne rickettsioses are directly relevant to the health protection goals defined by the Centers for Disease Control and Prevention. Tick-borne rickettsial pathogens not only have the potential to affect the health of all segments of the population, but also can be used as biological weapons in case of a terrorist attack. Dr. Fikrig will mentor the scientific development of Dr. Pedra. Dr. Fikrig is a Professor of Medicine, Microbial Pathogenesis and Public Health at Yale University and a recognized leader in the field of tick-borne diseases. The research will focus on the mechanisms of immunity against Anaplasma phagocytophilum and Rickettsia conorii, two pathogens from the tick-borne rickettsial group. The mechanisms of immunity against A. phagocytophilum and R. conorii are largely unknown. Preliminary results shown by Dr. Pedra have demonstrated that Nod-like receptors play a critical role against A. phagocytophilum infection. Nod-like receptors recognize intracellular pathogens and trigger the cytokines IL-1b and IL-18 through their effect on the protease caspase-1. The research proposal described in this application aims to (1) examine the exact mechanism that triggers caspase-1 activation upon A. phagocytophilum infection; (2) assess the role of caspase-1/IL-18 in the adaptive immune response against A. phagocytophilum; and (3) identify the Nod-like receptor that triggers caspase-1 activation upon R. conorii infection. To accomplish these goals, Dr. Pedra will have free access to the modern facilities present at Yale University and will make use of the most current techniques available in immunobiology, microbial pathogenesis and proteomics.