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

描述（由申请人提供）：此提案描述了公共卫生研究领域为期三年的监督职业发展计划。Joap Pedra博士在普渡大学完成了他的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”，扩大了他在免疫生物学领域的科学技能。Pedra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确定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，而且在发生恐怖袭击时还可以用作生物武器。菲克里格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。该研究将重点研究对来自蜱传立克次体群的两种病原体——嗜吞噬细胞无形体和康氏立克次体的免疫机制。对嗜吞噬细胞单胞菌和conorii单胞菌的免疫机制在很大程度上是未知的。Pedra博士的初步结果表明，nod样受体在对抗嗜吞噬细胞芽胞杆菌感染中起着关键作用。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计划旨在(1)研究在嗜吞噬细胞芽胞杆菌感染时触发caspase-1激活的确切机制；(2)评估caspase-1/IL-18在抗嗜吞噬细胞芽胞杆菌适应性免疫应答中的作用；(3)鉴定conconi感染时触发caspase-1激活的nod样受体。为了实现这些目标，Pedra博士将可以免费使用耶鲁大学现有的现代化设施，并将利用免疫生物学、微生物发病机制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.