Mentored Patient Oriented Research in Lung Transplantation

描述(由申请人提供)：这项以患者为中心的研究的职业生涯中期研究人员奖的目标是提高克里斯蒂博士培训、指导和支持从事肺部和重症护理医学患者导向研究的内科科学家的职业发展的能力。这些目标将通过持续减少克里斯蒂博士的临床和行政责任来实现，从而增加直接用于指导活动的努力，扩大克里斯蒂博士的研究计划以纳入更长期的结果，以及获得新的研究和指导技能。克里斯蒂博士研究肺移植后急性肺损伤(称为原发移植物功能障碍，PGD)的成功研究计划将扩大，为受训者提供密集的研究体验，并辅之以针对每个受训者的职业发展活动，包括学位课程的教学课程、研究研讨会、拨款撰写研讨会和负责任的研究行为培训。拟议的K24研究将解决这样的假设，即PGD可以在手术前使用上皮损伤和TH17反应的分子标记物进行预测，并且PGD中肺损伤的这些分子机制与随后的毛细支气管炎闭塞性综合征(BOS)风险有关。PGD是发生在肺移植后的严重急性肺损伤，对早期发病率、死亡率和费用有重要影响。此外，最近的研究将PGD与BOS的增加联系在一起，BOS是同种异体肺移植功能障碍的临床形式，也是肺移植长期发病率和死亡率的主要来源。对于观察到的PGD和BOS之间的联系，一个主要的假说是，移植物早期上皮损伤并伴有异常修复和恢复会导致持续性损伤、炎症和BOS。在目标1下，我们将确定和验证循环蛋白生物标记物对PGD上皮损伤和TH17反应的预测作用 在肺移植受者手术前测量时。在目标2下，我们将确定术后早期测量的上皮损伤和TH17反应的循环蛋白生物标记物与随后发生的闭塞性毛细支气管炎综合征(BOS)的关系。我们的目标的实现将扩大Christie博士的研究平台，将BOS和其他长期结果纳入其中，并为受训者提供一个研究平台，以测试预防PGD的新疗法，并确定PGD与长期移植结果之间的联系机制。

DESCRIPTION (provided by applicant): The goals of this Midcareer Investigator Award in Patient-Oriented Research are to enhance the ability of Dr. Christie to train, mentor and support the career development of physician scientists pursuing patient oriented research in pulmonary and critical care medicine. These goals will be accomplished through sustained reduction in Dr. Christie's clinical and administrative responsibilities with a resultant increase in effort spent directly on mentoring activities, expanding Dr. Christie's research program to include longer-term outcomes, and acquisition of new research and mentoring skills. Dr. Christie's successful research program investigating acute lung injury following lung transplantation (termed primary graft dysfunction, PGD) will be expanded to provide trainees with an intensive research experience complemented by career development activities specific to each trainee including didactic coursework in degree programs, research seminars, grant writing workshops, and training in responsible conduct of research. The proposed K24 research will address the hypothesis that PGD can be predicted using molecular markers of epithelial injury and TH17 response pre- operatively, and that these molecular mechanisms of lung injury in PGD are linked to subsequent bronchiolitis obliterans syndrome (BOS) risk. PGD is severe acute lung injury occurring in the days after lung transplantation and has a major impact on early morbidity, mortality, and cost. Furthermore, recent studies have linked PGD to increased incidence of BOS, the clinical form of lung allograft dysfunction and the major source of long-term morbidity and mortality in lung transplantation. A leading hypothesis for the observed link of PGD and BOS is that early epithelial injury to the allograft with aberrant repair and recovery leads to persistent injury, inflammation and BOS. Under Aim 1 we will determine and validate the predictive utility of circulating protein biomarkers of epithelial injury and TH17 response for PGD when measured pre-operatively in lung transplant recipients. Under Aim 2 we will determine the association of circulating protein biomarkers of epithelial injury and TH17 response measured in the early post-operative period with subsequent development of Bronchiolitis Obliterans Syndrome (BOS). Fulfillment of our aims will expand Dr. Christie's research platform to include BOS and other long-term outcomes, and provide a research platform for trainees to test novel therapies for PGD prevention, and define mechanisms of the link between PGD and longer-term transplant outcomes.