Mentored Patient Oriented Research in Lung Transplantation

描述（由申请人提供）：这个以患者为导向的研究中期研究者奖的目标是提高克里斯蒂博士的能力，以培训，指导和支持在肺部和重症监护医学领域进行以患者为导向的研究的医生科学家的职业发展。这些目标将通过持续减少Christie博士的临床和行政职责来实现，从而增加直接用于指导活动的努力，扩大Christie博士的研究计划，以包括长期成果，并获得新的研究和指导技能。克里斯蒂博士成功的研究计划调查肺移植后的急性肺损伤（称为原发性移植物功能障碍，PGD）将扩大到为学员提供密集的研究经验，并辅之以针对每个学员的职业发展活动，包括学位课程的教学课程，研究研讨会，赠款写作研讨会和负责任的研究行为培训。拟议的K24研究将解决以下假设：可以使用上皮损伤的分子标志物和术前TH17反应预测PGD，并且PGD中肺损伤的这些分子机制与随后的闭塞性细支气管炎综合征（BOS）风险相关。PGD是肺移植后发生的严重急性肺损伤，对早期发病率、死亡率和费用有重大影响。此外，最近的研究表明PGD与BOS发病率增加有关，BOS是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，一个主要的假设是，早期上皮损伤的同种异体移植物异常修复和恢复导致持续的损伤，炎症和BOS。在目标1下，我们将确定并验证循环蛋白质生物标志物对PGD的上皮损伤和TH17反应的预测效用 在肺移植受者术前测量时。在目标2下，我们将确定在术后早期测量的上皮损伤和TH17反应的循环蛋白质生物标志物与闭塞性细支气管炎综合征（BOS）的随后发展的关联。我们的目标的实现将扩大克里斯蒂博士的研究平台，包括BOS和其他长期结果，并为学员提供一个研究平台，以测试预防PGD的新疗法，并确定PGD和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.