TSP-1: A mediator of sepsis-induced lung injury

描述（由申请人提供）： 该提案代表了一个为期五年的课程和研究计划，旨在将候选人从目前的指导工作台研究重点转变为独立研究者驱动的临床研究。该计划为期五年，以促进适当的课堂工作以及具体研究目标的执行。广义上，主要目标是确认目前在体外假设在人类与败血症的临床症状和完整的课程在临床研究科学。候选人目前的研究集中在炎症细胞募集在肺部疾病中的作用。脓毒症具有非常高的相关死亡率，并且其发病率可能正在上升。肺损伤是严重脓毒症中最常见的器官功能障碍之一。已知转化生长因子β（TGF β）存在于早期肺损伤中，并且可能用于修复初始肺损伤。已知在脓毒症中重要的血管事件包括炎症和凝血级联反应的启动。由这些级联反应引起的炎症和修复之间的平衡可能对肺损伤的解决至关重要。因此，这些级联反应的终产物可能在影响严重脓毒症的器官功能障碍过程中发挥潜在作用。血栓反应蛋白-1（TSP-1）在人类败血症中增加，但其含义尚未完全清楚。因为已知TSP-1与潜伏的TGF-β相互作用并激活，所以其存在可能用于启动修复严重脓毒症中的急性肺损伤所必需的TGF-β应答。具体目的：研究TSP-1是否在调节脓毒症诱导的急性肺损伤过程中起重要作用。假设1.1：在人类脓毒症中，TSP-1水平升高与随后的TGF β 1升高相关。假设1.2：在人类脓毒症中，TSP-1水平升高与肺损伤发生率降低和病程缩短相关。假设1.3：TSP-1基因中Asn 682 Ser多态性的患者将具有更高的肺损伤发生率和更严重的病程。通过这些研究，可以确定TSP-1和TGF-β相互作用对脓毒症患者ARDS发展的重要性、临床相关性和潜在影响。该补助金的开发部分旨在促进申请人成为ARDS和败血症领域独立资助的临床研究人员的职业目标。该机构（三级保健医院，GCRC和医学与公共卫生学院）的综合资源将提供给候选人，以实现这些目标。

DESCRIPTION (provided by applicant): This proposal represents a five-year curriculum and research plan that is designed to transition the candidate from his current mentored-bench research focus to one of independent investigator driven clinical research. The plan is five years in duration to facilitate the appropriate class work as well as the execution of the specific research objectives. Broadly, the main objectives are to confirm current in vitro hypotheses in humans with clinical signs of sepsis and complete coursework in clinical research sciences. The candidate's current research has centered on the role of inflammatory cell recruitment in lung disease. Sepsis has a very high associated mortality and its incidence may be rising. Lung injury is one of the more common organ dysfunctions present in severe sepsis. Transforming Growth Factor Beta (TGFb) is known to be present in early lung injury and may be serving to repair the initial pulmonary insult. Vascular events known to be important in sepsis include inflammation and initiation of the coagulation cascade. The balance between inflammation and repair caused by these cascades may be critical to resolution of lung injury. As a result, the end products of these cascades may have a potential role in affecting the course of organ dysfunction in severe sepsis. Thrombospondin-1 (TSP-1) is increased in human sepsis, but its implications are not fully understood. Because TSP-1 is known to interact with and activate latent TGF-beta, its presence may serve to initiate the TGF-beta response necessary to repair acute lung injury in severe sepsis. Specific Aim: To investigate whether TSP-1 is important in modulating the course of sepsis-induced acute lung injury. Hypothesis 1.1: In human sepsis, increased TSP-1 levels will be associated with subsequent increases in TGFbeta1. Hypothesis 1.2: In human sepsis, increased TSP-1 levels will be associated with a lower incidence and shorter course of lung-injury. Hypothesis 1.3: Patients with the Asn682Ser polymorphism in the TSP-1 gene will have a higher incidence of and a more severe course of lung injury. Through these studies, the importance, clinical relevance and potential implications of TSP-1 and TGF-beta interactions on the development of ARDS in septic patients can be determined. The development portion of this grant is designed to facilitate the applicant's career goals of becoming an independently funded clinical researcher in the area ARDS and sepsis. The combined resources of this institution (tertiary care hospital, GCRC and College of Medicine and Public Health) will be available to the candidate to achieve these goals.