Mentored Patient Oriented Research in Lung Transplantation

拟议的K24更新的目标是继续投入时间致力于 指导新的临床研究人员，从事职业发展，提升我自己 指导技能，并促进未来POR领导人向独立的过渡。这些目标 将通过持续减少克里斯蒂博士的临床和行政管理来实现 责任，从而增加了直接用于指导活动的努力， 扩大克里斯蒂博士的研究项目，以包括对捐赠者肺的进一步调查， 以及获得新的研究和指导技能。克里斯蒂博士成功的研究项目 研究肺移植后的急性肺损伤(称为原发移植物功能障碍， Pgd)将得到扩展，为学员提供密集的研究体验 通过职业发展活动，包括在学位课程中讲授课程，研究 研讨会、赠款撰写研讨会，以及负责任的研究行为培训。这个 拟议的K24研究更新将解决捐赠者吸烟暴露的假设 与上皮损伤和先天免疫激活有关，这种激活始于供者的原位， 而PGD可以用先天免疫、上皮损伤、 捐献者术前吸烟暴露。PGD是发生严重急性肺损伤的疾病 在肺移植后的日子里，并对早期发病率、死亡率和 成本。有证据表明，PGD是供者发生一系列伤害的最终结果 受者从脑死亡到再灌流期间的肺功能。因此，潜在的捐赠者 由于对PGD的担忧，器官经常被丢弃；进一步限制了 可供移植的器官。在目标1下，我们将确定捐赠者吸烟的联系 供者暴露于循环中的上皮损伤和天然免疫激活标志物 采购前，以及手术后的PGD。在目标2下，我们将确定和 验证循环蛋白生物标记物对上皮损伤、先天免疫的预测作用 在捐献者中，当术前测量时，PGD的激活和供者吸烟暴露。 我们目标的实现将使基于新的术前供体预测PGD成为可能 损伤和免疫的标记物，为供者天然免疫的作用提供了新的知识 PGD风险中的活化和上皮损伤，开发一个扩展的研究平台，包括 更详细的捐赠者特征，使对肺移植感兴趣的受试者受益 以及其他形式的肺损伤，并加强对克里斯蒂医生的新方法的培训 预测和内型测定，以及在指导方面的扩展培训。

The goals of the proposed K24 renewal are to continue to devote time to dedicated mentorship of new clinical investigators, engage in career development to enhance my own mentoring skills, and facilitate transition to independence for future POR leaders. 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 further investigation of the donor lungs, 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 including didactic coursework in degree programs, research seminars, grant writing workshops, and training in responsible conduct of research. The proposed renewal of the K24 research will address the hypotheses that donor smoke exposure is associated with epithelial injury and innate immune activation that begins in the donor in situ, and that PGD can be predicted using molecular markers of innate immunity, epithelial injury, and donor smoke exposure pre-operatively in donors. PGD is severe acute lung injury occurring in the days after lung transplantation and has a major impact on early morbidity, mortality, and cost. Evidence suggests that PGD is the end result of a series of injuries occurring in the donor lung from the time of brain death to reperfusion in the recipient. Therefore, potential donor organs are routinely discarded because of concern for PGD; further limiting the number of organs available for transplant. Under Aim 1, we will determine the association of donor smoke exposure with circulating markers of epithelial injury and innate immune activation in the donor prior to procurement, and with PGD post-operatively. Under Aim 2, we will determine and validate the predictive utility of circulating protein biomarkers of epithelial injury, innate immune activation, and donor smoke exposure for PGD when measured pre-operatively in donors. Fulfillment of our aims will enable prediction of PGD based on novel pre-operative donor markers of injury and immunity, provide new knowledge on the roles of donor innate immune activation and epithelial injury in PGD risk, develop an expanded research platform including more detailed donor characterization to benefit mentees interested in lung transplantation as well as in other forms of lung injury, and enhanced training for Dr. Christie in novel methods of prediction and endotype determination, as well as expanded training in mentoring.