The regulation and function of platelet FcARIIA in sepsis

项目总结/摘要 这是一份K 08奖的申请，申请人是伊丽莎白·米德尔顿博士，她是一名肺科和重症监护医生， 犹他州大学。米德尔顿博士正在建立自己作为一个年轻的研究人员在翻译研究 驱动脓毒症病理生理学的生物学机制。她的长期目标是确定新的 治疗目标，以促进脓毒症患者的护理，使他们有更长的时间， 提高生活质量。血小板在炎症和感染中的作用知之甚少。她是 建议研究巨核细胞（血小板母细胞）和血小板的贡献，以及如何 它们会影响病人对败血症的反应K 08将为米德尔顿博士提供必要的支持， 完成以下目标：1）获得巨核细胞（MK）生物学，基因表达， 功能评估，2）通过使用 人源化转基因小鼠模型，3）开发解剖细胞内血小板的技能和工具集 信号事件，4）扩展技能，独立领导和管理翻译研究计划。到 为了实现这些目标，米德尔顿博士组建了一个指导团队，其中包括一位主要的导师， Matthew Rondina是一位公认的医生-研究者，也是免疫系统中血小板生物学领域的领导者。 反应和炎症，和4名顾问谁是在巨核细胞基因表达领域的领导者， 生物学和功能，脓毒症和急性呼吸窘迫综合征的转化研究， 改变了老鼠的研究 脓毒症的主要治疗是早期识别和血流动力学复苏，抗生素和 支持性护理。尽管有医院为基础的系统来检测脓毒症的发作，但它仍然携带显著的 死亡率、短期和长期发病率。米德尔顿博士的研究重点是血小板免疫 受体，IgG受体IIA的Fc片段（FcγRIIA），位于止血交叉路口， 免疫和炎症连续体。Middleton博士将（目标1）确定血小板FcγRIIA表达如何影响 脓毒症中增加;（目的2）确定脓毒症期间血小板FcγRIIA增加是否导致过度活化， 血栓形成和死亡率。在目标1中，Middleton博士将研究炎症激动剂， 血小板FcγRIIA增加，并跟踪该受体从巨核细胞到循环的表达 血小板在目标2中，Middleton博士将研究血小板FcγRIIA增加是否会导致 血栓形成和与败血症相关的短期死亡率。这项研究将为米德尔顿博士设计 并实施具有临床适用性的研究计划，为脓毒症的未来治疗提供信息。

PROJECT SUMMARY/ABSTRACT This is an application for a K08 award for Dr. Elizabeth Middleton, a pulmonary and critical care physician at the University of Utah. Dr. Middleton is establishing herself as a young investigator in translational research of biological mechanisms driving the pathophysiology of sepsis. Her long-term goal is identification of new therapeutic targets to advance the care of patients suffering with sepsis so they have longer and have improved quality of life. The role of platelets in inflammation and infection is poorly understood. She is proposing to investigate the contribution of the megakaryocytes (the platelet parent cell) and platelets, and how they impact a patient’s response to sepsis. This K08 will provide Dr. Middleton with the support necessary to accomplish the following goals: 1) gain expertise in megakaryocyte (MK) biology, gene expression, and functional assessments, 2) to increase knowledge of platelet FcγRIIA biology and function through use of humanized transgenic mouse model, 3) to develop the skills and toolsets to dissect intracellular platelet signaling events, 4) expand skills to independently lead and manage a translational research program. To achieve these goals, Dr. Middleton has assembled a mentoring team comprising a primary mentor, Dr. Matthew Rondina, an established physician-investigator and leader in the field of platelet biology in immune responses and inflammation, and 4 advisors who are leaders in the fields of megakaryocyte gene expression, biology and function, translational research in sepsis and acute respiratory distress syndrome, and genetically altered murine research. The primary treatment for sepsis is early recognition and hemodynamic resuscitation, antibiotics and supportive care. Despite hospital-based systems to detect the onset of sepsis, it continues to carry significant mortality, short- and long-term morbidity. Dr. Middleton’s research focuses on the study of a platelet immune receptor, Fc fragment of IgG receptor IIA (FcγRIIA), which is positioned at the cross-roads hemostatic, immune, and inflammatory continuum. Dr. Middleton will (Aim 1) determine how platelet FcγRIIA expression is increased in sepsis; (Aim 2) determine if increased platelet FcγRIIA during sepsis causes hyperactivation, thrombosis, and mortality. In Aim 1, Dr. Middleton will investigate the inflammatory agonists that drive increases in platelet FcγRIIA and track the expression of this receptor from the megakaryocyte to circulating platelets. In Aim 2, Dr. Middleton will interrogate whether the increased platelet FcγRIIA contributes to risk of thrombosis and short-term mortality associated with sepsis. This research will prepare Dr. Middleton to design and implement a research program with clinical applicability to inform future therapies for sepsis.