The regulation and function of platelet FcARIIA in sepsis

项目摘要/摘要 这是伊丽莎白·米德尔顿博士的K08奖项申请书，她是一名肺部和重症监护内科医生，位于 犹他大学。米德尔顿博士在翻译研究方面确立了自己作为年轻研究员的地位 脓毒症病理生理学的生物学机制。她的长期目标是识别新的 治疗目标是推进脓毒症患者的护理，使他们有更长的时间和 提高了生活质量。人们对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)和血小板的作用，以及如何 它们会影响患者对败血症的反应。这款K08将为米德尔顿博士提供必要的支持 完成以下目标：1)获得巨核细胞生物学、基因表达和 功能评估，2)通过使用以下方法增加对血小板FcγRIA生物学和功能的了解 人源化转基因小鼠模型，3)开发解剖细胞内血小板的技术和工具集 信号事件，4)扩展独立领导和管理翻译研究项目的技能。至 为了实现这些目标，米德尔顿博士组建了一个指导团队，由一位主要导师Dr。 Matthew Rondina，免疫领域中血小板生物学领域的知名内科研究员和领导者 反应和炎症，以及在巨核细胞基因表达领域处于领先地位的4名顾问， 脓毒症和急性呼吸窘迫综合征的生物学和功能、翻译研究以及遗传学 改变了对老鼠的研究。 脓毒症的主要治疗方法是早期识别和血流动力学复苏，抗生素和 支持性护理。尽管以医院为基础的系统可以检测脓毒症的发病，但它仍然具有显著的 死亡率、短期和长期发病率。米德尔顿博士的研究重点是研究血小板免疫 受体，免疫球蛋白受体IIA的Fc片段(FcγRIIA)，位于十字路口止血， 免疫和炎症的连续体。米德尔顿博士将(目标1)确定血小板FcγRIIA的表达情况 脓毒症时升高；(目标2)确定脓毒症时血小板Fcγ升高是否导致过度激活， 血栓形成和死亡率。在目标1中，米德尔顿博士将研究推动炎症激动剂 从巨核细胞到循环的血小板FcγRIIA增加和跟踪该受体的表达 血小板。在目标2中，米德尔顿博士将询问增加的血小板FcγRIIA是否有助于 与脓毒症相关的血栓形成和短期死亡率。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，为未来脓毒症的治疗提供信息。

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.