Novel Platelet Functions in Sepsis and Venous Thromboembolism

脓毒症和静脉血栓栓塞中的血小板新功能

• 批准号: 7660622
• 负责人: Matthew Thomas Rondina
• 金额: $ 15.5万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660622
• 关键词: Biological Process; Biology; Blood Platelets; Coagulants; Coagulation Process; Commit; Data; Development; Development Plans; Environment; Flow Cytometry; Foundations; Funding; Health; Incidence; Inflammation; Instruction; Investigation; Leukocytes; Measures; Mentors; Messenger RNA; Molecular; Morbidity - disease rate; P-Selectin; Pathway interactions; Patient Care; Patients; Platelet Activation; Production; RNA Splicing; Research; Research Methodology; Research Personnel; Role; Scientist; Sepsis; Severity of illness; Structure; Surface; Thromboembolism; Thromboplastin; Thrombosis; Time; Training; Venous; career development; experience; human disease; improved; indexing; mRNA Precursor; monocyte; mortality; new therapeutic target; novel; responsible research conduct; symposium; thiazole orange

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.

描述（由申请人提供）：败血症是一种促凝的疾病，其特征是有害和广泛的炎症。尽管对白细胞和单核细胞的作用进行了充分的研究，但败血症中血小板生物学的数据很少。血小板功能的变化可能直接导致败血症的炎症和血栓形成。我的初步数据表明，从败血症患者中分离出的血小板会产生新的组织因子（TF）mRNA并加速凝块时间。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，血小板似乎具有败血症重要的生物学功能。在拟议的应用中，我将研究败血症患者和健康对照组中的血小板活动。我提出的研究将前瞻性地使特征化（1）用p-选择素流式细胞术测量的TF mRNA的新型合成（2）血小板激活，以及（3）用噻唑橙流式细胞仪测量的血小板周转率。我将确定这些血小板活动和功能是否可以预测败血症患者中的28天死亡率，明显的挖掘和静脉血栓栓塞（VTE）。我还将将败血症患者中的这些血小板活动与健康对照进行比较。这些研究可能会提供对人类疾病中血小板功能和活动的更多了解。这些新颖的观察结果将使我们能够进一步表征分子途径并开发败血症和VTE治疗的新疗法。这些研究以我们强大的初步数据为基础，并将在极其支持的环境中完成。我有两位具有强大研究和指导经验的导师，一个咨询小组，以其在炎症和血栓形成方面的专业知识，生产性研究的个人往绩以及一个完全忠诚的部门而获得全国认可。我还构建了一个职业发展计划，该计划在研究方法中结合了结构化的教学培训，参与正在进行的研究会议以及负责任的研究进行培训。这些研究不仅将为我们对败血症和VTE中血小板功能的理解做出重大贡献，而且还将为我奠定了从初级研究者到独立资助的临床医生科学家的基础。相关性（请参阅说明）：本应用程序中提出的研究将扩展我们对血小板如何影响败血症的发病率和死亡率的理解。这些研究最终可能提供新的治疗靶标，以改善我们对败血症患者的护理。