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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Midcareer Investigator Award in Patient-Oriented Research (K24)
Project #
5K24HL115354-08
Application #
9751924
Study Section
NHLBI Mentored Patient-Oriented Research Review Committee (MPOR)
Program Officer
Reineck, Lora A
Project Start
2012-08-03
Project End
2022-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Singer, Jonathan P; Diamond, Joshua M; Anderson, Michaela R et al. (2018) Frailty phenotypes and mortality after lung transplantation: A prospective cohort study. Am J Transplant 18:1995-2004
Gannon, Whitney D; Lederer, David J; Biscotti, Mauer et al. (2018) Outcomes and Mortality Prediction Model of Critically Ill Adults With Acute Respiratory Failure and Interstitial Lung Disease. Chest 153:1387-1395
Courtwright, Andrew M; Zaleski, Derek; Gardo, Lisa et al. (2018) Causes, Preventability, and Cost of Unplanned Rehospitalizations Within 30 Days of Discharge After Lung Transplantation. Transplantation 102:838-844
Harhay, Michael O; Porcher, Raphaël; Cantu, Edward et al. (2018) An Alternative Approach for the Analysis of Time-to-Event and Survival Outcomes in Pulmonary Medicine. Am J Respir Crit Care Med 198:684-687
Anderson, Brian J; Chesley, Christopher F; Theodore, Miranda et al. (2018) Incidence, risk factors, and clinical implications of post-operative delirium in lung transplant recipients. J Heart Lung Transplant 37:755-762
Panzer, Ariane R; Lynch, Susan V; Langelier, Chaz et al. (2018) Lung Microbiota Is Related to Smoking Status and to Development of Acute Respiratory Distress Syndrome in Critically Ill Trauma Patients. Am J Respir Crit Care Med 197:621-631
Meyer, Nuala J; Reilly, John P; Anderson, Brian J et al. (2018) Mortality Benefit of Recombinant Human Interleukin-1 Receptor Antagonist for Sepsis Varies by Initial Interleukin-1 Receptor Antagonist Plasma Concentration. Crit Care Med 46:21-28
Miano, Todd A; Cuker, Adam; Christie, Jason D et al. (2018) Comparative Effectiveness of Enoxaparin vs Dalteparin for Thromboprophylaxis After Traumatic Injury. Chest 153:133-142
Abbas, Arwa A; Young, Jacque C; Clarke, Erik L et al. (2018) Bidirectional transfer of Anelloviridae lineages between graft and host during lung transplantation. Am J Transplant :
Cantu, Edward; Diamond, Joshua M; Suzuki, Yoshikazu et al. (2018) Quantitative Evidence for Revising the Definition of Primary Graft Dysfunction after Lung Transplant. Am J Respir Crit Care Med 197:235-243

Showing the most recent 10 out of 59 publications