Monocyte Pyrin Expression in Human Sepsis

描述(由申请人提供)： 这份意见书描述了一个为期3年的分子生物学和分子遗传学综合培训计划，旨在为Mark W.Hall博士提供成为一名杰出的、独立的内科科学家的工具。这次培训，再加上他迄今为止对K12的支持，将使他获得必要的技能来研究儿科脓毒症的炎症调节。霍尔博士在匹兹堡儿童医院完成了儿科和儿科重症监护医学方面的医学培训，现在是俄亥俄州立大学/哥伦布儿童医院的助理教授。先天免疫生物学领域的领军人物马克·D·威尔斯博士将担任霍尔博士的赞助人和导师。在威尔斯博士和他的实验室工作人员的帮助下，霍尔博士从28名患有败血症导致的器官衰竭的儿童队列中产生了初步数据。这些数据表明，与死亡患者相比，存活患者的单核细胞对蛋白质派林的信使核糖核酸表达明显下调。吡喃是一种重要的调节蛋白，与家族性地中海热的炎症反应有关。吡喃及其基因MEFV在此之前没有被描述过。在获奖期内，我们期望：1)了解儿童严重脓毒症/感染性休克患者中单核细胞MEFV mRNA表达、单核细胞派林蛋白表达与死亡率之间的关系；2)了解在儿童严重败血症/感染性休克患者中，单核细胞MEFV基因表达水平与mRNA降解之间的关系；以及3)检验以下假设，即在儿童严重败血症/感染性休克患者中，单核细胞MEFV基因表达减少与MEFV基因存在顺式作用多态有关。为了实现这一最终目标，并为霍尔博士提供坚实的分子遗传学基础，他将花时间在沃尔夫冈·萨迪博士的实验室进行培训和实验，沃尔夫冈·萨迪博士是调节基因多态领域的世界专家。哥伦布儿童研究所、戴维斯心肺研究所和俄亥俄州立大学的联合设施提供了无与伦比的科学资源，为霍尔博士的学术和科学发展提供了理想的环境。 (摘要结束)

DESCRIPTION (provided by applicant): This submission describes a comprehensive 3 year training program in molecular biology and molecular genetics designed to provide Dr. Mark W. Hall with the tools to become an outstanding, independent physician-scientist. This training, combined with his K12 support to date, will give him the necessary skills to investigate the regulation of inflammation in pediatric sepsis. Dr. Hall completed his medical training in Pediatrics and Pediatric Critical Care Medicine at Children's Hospital of Pittsburgh and is now Assistant Professor at The Ohio State University / Columbus Children's Hospital. Dr. Mark D. Wewers, a leader in the field of innate immunobiology, will serve as Dr. Hall's sponsor and mentor. Dr. Hall has generated, with the help of Dr. Wewers and his laboratory staff, preliminary data from a cohort of 28 children with sepsis-induced organ failure. These data show that monocytes in survivors demonstrate a marked downregulation of mRNA for the protein pyrin compared to nonsurvivors. Pyrin is an important regulatory protein which is associated with inflammation in the disease familial Mediterranean fever. Pyrin and its gene MEFV have not been described in this context before. In the course of the award period we expect to: 1) understand the associations between monocyte MEFV mRNA expression, monocyte pyrin protein expression, and mortality in the setting of pediatric severe sepsis/septic shock, 2) understand the role of mRNA production versus mRNA degradation in determining MEFV mRNA levels in survivors versus nonsurvivors of pediatric severe sepsis/septic shock, and 3) test the hypothesis that reduction in monocyte MEFV mRNA expression in the setting of pediatric severe sepsis/septic shock is associated with the presence of a cis-acting polymorphism in the MEFV gene. In order to accomplish this final goal, and to provide Dr.Hall with a robust foundation in molecular genetics, he will spend time in training and experimentation in the laboratory of Dr. Wolfgang Sadee, a world expert in the area of regulatory genetic polymorphisms. The combined facilities of Columbus Children's Research Institute, the Davis Heart and Lung Research Institute, and The Ohio State University offer an unparalleled array of scientific resources and provide an ideal setting for Dr. Hall's academic and scientific development. (End of Abstract)