Novel Platelet Functions in Sepsis and Venous Thromboembolism

描述(申请人提供)：败血症是一种促凝血剂疾病，其特征是损伤和广泛的炎症。尽管白细胞和单核细胞的作用已被很好地研究，但关于脓毒症中的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的炎症和血栓形成。我的初步数据显示，从脓毒症患者分离的血小板会产生新的组织因子(TF)mRNA，并加速凝血时间。我的数据还表明，转铁蛋白mRNA的产生与疾病的严重程度和死亡率有关。因此，血小板似乎在脓毒症中具有重要的生物学功能。在提议的应用中，我将研究脓毒症患者和健康对照组的血小板活性。我提出的研究将前瞻性地描述(1)新的TF mRNA的合成，(2)P-选择素流式细胞术测量的血小板活化，(3)用噻唑橙流式细胞术测量的血小板转换率。我将确定这些血小板活性和功能是否可以预测脓毒症患者28天的死亡率、明显的DIG和静脉血栓栓塞症(VTE)。我还会将脓毒症患者的这些血小板活性与健康对照组进行比较。这些研究可能对人类疾病中的血小板功能和活性有更多的了解。这些新颖的观察结果将使我们能够进一步确定分子途径，并开发治疗脓毒症和静脉血栓栓塞症的新疗法。这些研究建立在我们强有力的初步数据基础上，并将在一个极其有利的环境中完成。我有两位导师，他们有丰富的研究和指导经验，他们的顾问小组因其在炎症和血栓形成方面的专业知识而在全国范围内得到认可，他们个人在生产性研究方面的记录，以及一个全心全意投入的部门。我还构建了一个职业发展计划，其中包括研究方法方面的有组织的说教培训，参加正在进行的研究会议，以及负责任的研究行为培训。这些研究不仅将为我们了解脓毒症和静脉血栓栓塞症中的血小板功能做出重大贡献，也将为我从初级研究员晋升为一名独立资助的临床科学家奠定基础。相关性(见说明书)：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的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.