Novel Platelet Functions in Sepsis and Venous Thromboembolism

描述（由申请人提供）：脓毒症是一种促凝血疾病，其特征是损伤性和广泛性炎症。虽然白细胞和单核细胞的作用已被充分研究，但关于血小板在脓毒症中的生物学作用的数据还很缺乏。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。我的初步数据表明，从脓毒症患者分离的血小板产生新的组织因子（TF）mRNA，并加速凝血时间。我的数据还表明TF mRNA的产生与疾病的严重程度和死亡率相关。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。我的研究将前瞻性地描述（1）TF mRNA的新合成，（2）用P-选择素流式细胞术测量血小板活化，（3）用噻唑橙子流式细胞术测量血小板周转。我将确定这些血小板活性和功能是否预测败血症患者的28天死亡率、明显DIG和静脉血栓栓塞（VTE）。我还将比较脓毒症患者和健康对照者的血小板活性。这些研究可能会提供更多的了解血小板的功能和活动在人类疾病。这些新的观察结果将使我们能够进一步表征分子途径，并开发治疗脓毒症和VTE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。我有两个导师，他们有很强的研究和指导经验，一个咨询小组，他们在炎症和血栓形成方面的专业知识得到了国家的认可，一个富有成效的研究的个人记录，和一个完全致力于部门。我还建立了一个职业发展计划，其中包括结构化的，教学培训的研究方法，参与正在进行的研究会议，并在负责任的研究行为的培训。这些研究不仅将为我们理解脓毒症和VTE中的血小板功能做出重大贡献，而且还将为我从初级研究者晋升为独立资助的临床科学家奠定基础。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脓毒症发病率和死亡率的理解。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的护理。

DESCRIPTION (provided by applicant): 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.