Novel Platelet Functions in Sepsis and Venous Thromboembolism

脓毒症是一种促凝血疾病，其特征是损伤性和广泛的炎症。虽然 虽然白细胞和单核细胞的作用已被充分研究，但关于脓毒症中血小板生物学的数据很少。 血小板功能的改变可能直接导致脓毒症中的炎症和血栓形成。我 初步数据表明，从脓毒症患者中分离的血小板产生新的组织因子（TF）， mRNA和加速凝血时间。我的数据还表明TF mRNA的产生与疾病有关， 严重程度和死亡率。因此，血小板似乎在脓毒症中具有重要的生物学功能。 在拟议的申请中，我将研究败血症患者和健康对照者的血小板活性。我 拟开展的研究将前瞻性地表征（1）TF mRNA的新合成，（2）血小板活化 用P-选择素流式细胞术测量，和（3）用噻唑橙子流式细胞术测量血小板周转率 细胞仪我将确定这些血小板活性和功能是否能预测28天死亡率、明显的DIG， 脓毒症患者的静脉血栓栓塞（VTE）。我也将比较这些血小板活动在败血症 患者健康控制。这些研究可能提供对血小板功能的进一步了解 和人类疾病的活动。这些新的观察将使我们能够进一步表征分子 途径，并开发治疗败血症和静脉血栓栓塞的新疗法。 这些研究建立在我们强大的初步数据基础上，并将在一个非常支持的环境中完成。 环境我有两个导师，他们有很强的研究和指导经验，一个顾问小组， 国家承认他们在炎症和血栓形成方面的专业知识， 研究，和一个完全致力于部门。我还制定了一个职业发展计划， 结合了结构化的，教学培训的研究方法，参与正在进行的研究会议， 以及负责任地进行研究的培训。这些调查不仅将提供重要的 有助于我们理解脓毒症和VTE中的血小板功能，但也将为 我从初级研究员晋升为独立资助的临床科学家。 相关性（参见说明）： 本申请中提出的研究将扩大我们对血小板如何影响发病率的理解 和败血症的死亡率。这些研究可能最终提供新的治疗靶点，以改善我们对 脓毒症患者

Sepsis is a pro-coagulant illness characterized by injurious and widespread inflammation. Although the role of leukocytes and monocytes is well studied, there is a paucity of data on platelet biology in sepsis. Changes in platelet function may contribute directly to inflammation and thrombosis in sepsis. My preliminary data demonstrate that platelets isolated from sepsis patients produce new tissue factor (TF) mRNA and accelerate clot times. My data also shows that TF mRNA production correlates with illness severity and mortality. Thus, platelets appear to have biological functions important in sepsis. In the proposed application, I will study platelet activites in sepsis patients and healthy controls. My proposed studies will prospectively charaterize (1) novel synthesis of TF mRNA, (2) platelet activation measured with P-selectin flow cytometry, and (3) platelet turnover measured with thiazole orange flow cytometry. I will determine if these platelet activities and functions predict 28-day mortality, overt DIG, and venous thromboembolism (VTE) in sepsis patients. I will also compare these platelet activities in sepsis patients to health controls. These investigations may provide additional understanding of platelet functions and activities in human diseases. These novel observations will allow us to further characterize molecular pathways and to develop new therapies in the treatment of sepsis and VTE. These studies build on our robust preliminary data and will be accomplished in an extremely supportive environment. I have two mentors with strong research and mentoring experience, an advisory panel with national recognition for their expertise in inflammation and thrombosis, an personal track record of productive research, and a fully committed department. I also have constructed a career-development-plan that incorporates structured, didactic training in research methods, participation in ongoing research conferences, and training in the responsible conduct of research. These investigations will not only provide significant contributions to our understanding of platelet functions in sepsis and VTE, but will also lay the foundation for me to advance from junior investigator to an independently-funded clinician-scientist. RELEVANCE (See instructions): The research proposed in this application will expand our understanding of how platelets influence morbidity and mortality in sepsis. These studies may ultimately provide new therapeutic targets to improve our care of patients with sepsis.