The overall goal of this K23 Career Development Award is to become familiar with and enable improved understanding of alcohol's role on underlying mechanisms which may accelerate allograft dysfunction and the development of chronic rejection in recipients of donors with alcohol abuse. In lung transplantation, little is known about the influence of donor alcohol abuse on lung allograft function, and therefore the consequences to the recipient's lung transplant outcomes are virtually unknown. Our preliminary data revealed strikingly worse outcomes and more severe development of primary graft dysfunction in recipients of lung allografts from alcoholic donors. Thus, this project would add novel insights to the fields of alcohol research and lung transplantation, and ultimately innovative new preventative strategies and development of therapeutics to improve lung allografts resulting from this project would not only improve lung health in lung transplant recipients, but would also significantly decrease healthcare expenditures. This proposed project will extend our compelling preliminary data demonstrating increased allograft dysfunction in lung transplant recipients who receive allografts from donors with alcohol abuse. Lung dysfunction early after transplant is evident by prolonged use of mechanical ventilation and hospitalizations. Gas exchange in the lung allograft is markedly worse in those recipients with alcoholic donors. Further research will enable us to examine the pro-inflammatory and oxidative stresses experienced by lung allografts of chronic alcoholics prior to, immediately following, and after one year following lung transplantation. Our hypothesis is that donor alcohol use has negative effects on the human lung allograft in transplantation and is detrimental to allograft function bot early following transplant, and later leading to increased chronic rejection, known as bronchiolitis obliterans syndrome. Our hypothesis will be tested in Specific Aims designed to 1) determine the epidemiology of alcohol use and abuse in donors of lung allografts, 2) examine effects on lung transplant outcomes such as acute rejection, development of infections and chronic rejection;and 3) determine whether alcohol mediated pro-inflammatory biomarkers and alcohol mediated oxidative stress markers in bronchoalveolar lavage fluid develop exaggerated responses after the ischemia-reperfusion stresses of lung transplantation. The proposed studies will determine how alcohol abuse in donors effects the lung allograft at the time of transplant, immediately following transplant and long-term following transplant. This research will provide preliminary evidence for my future R01 application, where, based on my findings in this proposed project, I intend to develop strategies and interventions in donors and lung transplant recipients for improvement in short and long-term functioning of the lung allograft. If we identify a potential target for intervention, we will plan a multi-center clinical trial to determine if suc intervention improves allograft function following lung transplantation. My career goal is to develop a translational research program focusing on the pulmonary effects of alcohol. Specifically, I will investigate human lung donor alcohol abuse for eventual development of preventative and therapeutic interventions to improve organ allocation and allograft function following lung transplantation. Building on a foundation of laboratory, clinical and formal coursework during fellowship, I will undergo intensive training in alcohol, immunology and transplant research. Outlined in my career development plan, my training will include additional coursework, individual mentorship, and presentations at national meetings. I will be mentored by the most successful mentor on campus, Dr. Elizabeth Kovacs, and in addition, the Advisory Committee I have assembled, including Drs. David Guidot, Ellen Burnham, Carol Schermer, and Rebecca Shilling, will complement Dr. Kovacs'resources by providing additional sources for career development and mentoring. This environment and mentorship will ensure my successful transition into an independent investigator. The strengths of this application include my comprehensive career development plan, the novel research hypothesis and design, the experience and commitment of my mentor and Advisory Committee members, and the strong institutional resources and support available to me at LUC. In addition, my proposed research is innovative and will serve as a launching pad for the development of my independent career. With the support of the K23 Award, I will gain the experience and skills required to achieve independence and my goal of becoming a leader in pulmonary alcohol research.
We anticipate that the research proposed will provide novel and critically important insights into how unhealthy alcohol use in donors subsequently affects the recipient of lung transplantation. This understanding will enable us to 1) gain a better understanding of the donor physiology, 2) allow us to prepare for complications in the recipient following transplantation, and 3) to then develop targeted interventions to decrease the likelihood of allograft dysfunction following transplantation by allowing for donor conditioning, or therapeutically optimizing the donor lung prior to transplant. Novel insights gained by the proposed application will enable improved outcomes for recipients following lung transplantation.
|Bharat, Ankit; Cunningham, Scott A; Scott Budinger, G R et al. (2015) Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans. Sci Transl Med 7:284re3|
|Lowery, Erin M; Kuhlmann, Erica A; Mahoney, Erin L et al. (2014) Heavy alcohol use in lung donors increases the risk for primary graft dysfunction. Alcohol Clin Exp Res 38:2853-61|