Monocyte Pyrin Expression in Human Sepsis

描述（由申请人提供）： 本申请描述了一个为期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。霍尔与工具，成为一个杰出的，独立的物理学家，科学家。这项培训，结合他迄今为止对K12的支持，将为他提供必要的技能，以研究儿科败血症中炎症的调节。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的医学培训，现在是俄亥俄州州立大学/哥伦布儿童医院的助理教授。 Mark D博士Wewers是先天免疫生物学领域的领导者，将担任Hall博士的赞助商和导师。在Wewers博士和他的实验室工作人员的帮助下，Hall博士已经从一组28名败血症引起的器官衰竭儿童中获得了初步数据。这些数据显示，与非存活者相比，存活者中的单核细胞显示蛋白质pyrin的mRNA显著下调。Pyrin是家族性地中海热中与炎症相关的重要调节蛋白。Pyrin及其基因MEFV在此背景下以前没有描述过。在授予期间，我们希望：1）了解单核细胞MEFV mRNA表达、单核细胞pyrin蛋白表达和儿科严重脓毒症/脓毒性休克背景下死亡率之间的关联，2）了解mRNA产生与mRNA降解在确定儿科严重脓毒症/脓毒性休克存活者与非存活者中MEFV mRNA水平中的作用，和3）检验在儿科严重脓毒症/脓毒性休克的情况下单核细胞MEFV mRNA表达的减少与MEFV基因中存在顺式作用多态性相关的假设。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，他将花时间在调节遗传多态性领域的世界专家沃尔夫冈·萨迪博士的实验室进行培训和实验。哥伦布儿童研究所、戴维斯心肺研究所和俄亥俄州州立大学的综合设施提供了无与伦比的科学资源，并为霍尔博士的学术和科学发展提供了理想的环境。 (End摘要）

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)