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.
Lung transplantation is a life-saving therapy for many people with advanced lung diseases. Primary graft dysfunction (PGD) is a form of acute lung injury occurring in the days after the transplant that causes the highest early mortality and appears to start in the donor lung prior to procurement. Through this Mid-Career Mentoring Award in Patient Oriented Research, the applicant will perform research and train junior physician-researchers to better predict PGD before the operation, and to understand the mechanisms of PGD beginning in the donor lung. This project may lead to new donor assessment tools and to targeted PGD prevention treatments that may increase the life span of lung transplant recipients.
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