Mentored Patient Oriented Research in Lung Transplantation

拟议的K24更新的目标是继续投入时间， 指导新的临床研究者，从事职业发展，以提高我自己的 指导技能，并促进未来POR领导人向独立过渡。这些目标 将通过持续减少克里斯蒂博士的临床和行政费用来实现 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计划，包括进一步调查捐赠者的肺， 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（称为原发性移植物功能障碍， PGD）将扩大，为学员提供密集的研究经验， 通过职业发展活动，包括学位课程的教学课程，研究 研讨会、赠款撰写讲习班和负责任地开展研究的培训。的 K24研究的拟议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，先天免疫激活始于供体原位， 并且PGD可以使用先天免疫，上皮损伤， 和供体术前暴露于供体烟雾。PGD是指发生在急性肺损伤后 在肺移植后的日子里，对早期发病率、死亡率和 成本有证据表明，PGD是供体发生的一系列损伤的最终结果 从脑死亡到受体再灌注的肺。因此，潜在捐助者 由于对PGD的关注，器官被常规地丢弃;进一步限制了 可供移植的器官。在目标1下，我们将确定供体吸烟 暴露于供体中上皮损伤和先天免疫激活的循环标志物 采购前和术后PGD。根据目标2，我们将确定和 验证上皮损伤、先天性免疫和免疫缺陷的循环蛋白质生物标志物的预测效用。 激活，和供体烟雾暴露的PGD时，术前测量供体。 我们目标的实现将使基于新的术前供体的PGD预测成为可能 损伤和免疫的标志物，提供了关于供体先天免疫的作用的新知识， 激活和上皮损伤的PGD风险，发展一个扩大的研究平台，包括 更详细的供体特征，以使对肺移植感兴趣的学员受益， 以及其他形式的肺损伤，并加强克里斯蒂博士在新的方法， 预测和内型测定，以及扩大的指导培训。

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.