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

描述(由申请人提供)： 这项提案代表了一项为期五年的课程和研究计划，旨在将候选人从目前的指导式长凳研究重点过渡到独立调查员驱动的临床研究。该计划为期五年，以促进适当的班级工作以及具体研究目标的执行。总的来说，主要目标是确认目前在人类体内有败血症临床迹象的体外假说，并完成临床研究科学的课程。这位候选人目前的研究重点是炎症细胞募集在肺部疾病中的作用。脓毒症有很高的相关死亡率，其发病率可能会上升。肺损伤是严重脓毒症最常见的器官功能障碍之一。已知转化生长因子β(TGFb)存在于早期肺损伤中，可能有助于修复最初的肺损伤。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是解决肺损伤的关键。因此，这些级联反应的最终产物可能在严重脓毒症的器官功能障碍过程中发挥潜在的作用。凝血酶敏感蛋白-1(TSP-1)在人类败血症中升高，但其意义尚不完全清楚。由于已知TSP-1与潜在的转化生长因子-β相互作用并激活，它的存在可能有助于启动修复严重脓毒症急性肺损伤所必需的转化生长因子-β反应。目的：探讨TSP-1在脓毒症所致急性肺损伤中的作用。假设1.1：在人类败血症中，TSP-1水平的升高将与随后的TGFbeta1的增加相关。假设1.2：在人类败血症中，TSP-1水平升高与较低的发生率和较短的肺损伤病程相关。假设1.3：TSP-1基因Asn682Ser多态的患者将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和转化生长因子-β相互作用在脓毒症患者ARDS发生中的重要性、临床相关性和潜在意义。这项资助的发展部分旨在促进申请者成为ARDS和脓毒症领域独立资助的临床研究人员的职业目标。该机构(三级护理医院、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.