The purpose of the K23 application is to develop myself into a successful independent investigator conducting patient-oriented research in transplant pharmacogenomics. As a transplant nephrologist and faculty member of at Vanderbilt University, my background includes an advanced degree in patient-oriented research (Master of Science in Clinical Investigation, MSCI) and formal clinical training in nephrology and kidney transplant. My K23 application builds on this background through a structured mentored program and didactic coursework to provide cross-training in pharmacology, genetics and genetic epidemiology, biostatistics, and clinical research to achieve my immediate and long-term goals. My five-year goal is to become an expert in transplant pharmacogenomics focused on the underlying genetic factors that affect individual variation in tacrolimus disposition and toxicities, particularly in relation to abnormal glucose metabolism and new onset diabetes after transplant (NODAT). My long-term goal is to become an independent physician scientist capable of conducting large patient-oriented research studies and clinical trials to bring personalized medicine into clinical practice in the transplant population. To successfully transition to independent extramural funding, I require continued strong mentorship. In this proposal, we delineate a training and research plan that benefits from dual mentorship through the Clinical and Translational Science Award (CTSA) group and the Pharmacogenomics Research Network (PGRN), as well as the collaborative milieu of Vanderbilt, to provide a comprehensive mentored educational and research experience. My CTSA mentor, Dr. T. Alp Ikizler, is an internationally recognized leader on the metabolic complications of kidney disease and expert in the methodology of patient- based clinical research, serving as the director of the MSCI program and chair of the Scientific Review Committee for the CTSA, with outstanding success in training young investigators. My PGRN mentor, Dr. Dan Roden, leads Vanderbilt's personalized medicine initiative as a world-renowned expert and pioneer in pharmacogenomics and personalized medicine through his work in life-threatening arrhythmias. The research project focuses my efforts on the investigation of genetic factors that affect response to tacrolimus, the most widely used immunosuppressant medication in kidney transplant recipients. Patients require the drug daily to prevent rejection of the transplanted organ, but therapy is complicated by its narrow therapeutic index, need for therapeutic drug monitoring, high inter-individual variability, and associated toxicities. Toxicities include increased risk for hyperglycemia and new onset diabetes after transplant (NODAT). These conditions are clinically important because they are independent risk factors for increased cardiovascular disease in kidney transplant patients, which is the number one cause of death in patients with a functioning transplant. We will test the hypothesis that frequent polymorphisms in ADME (absorption, distribution, metabolism and/or elimination) and non-ADME genes confer increased risk for abnormal glucose homeostasis in kidney transplant recipients treated with tacrolimus. The mentoring, career development, and research plans dovetail to maximize my ability to test this hypothesis in a concise manner and provide a framework for future investigations. To test our hypothesis, we will perform genetic association studies using both genome-wide and candidate gene approaches.
Aim 1 will identify genetic variants associated with abnormal glucose metabolism in kidney transplant recipients on tacrolimus using Vanderbilt's DNA biobank, BioVU, and its lined de-identified electronic medical record in a genome-wide study.
Aim 2 will use the same resources to find whether gene variants associated with abnormal glucose metabolism in kidney transplant recipients are associated with tacrolimus pharmacokinetics.
Aim 3 will characterize relationships between candidate genes implicated in tacrolimus disposition and/or action with markers of insulin secretion, insulin sensitivity, adipokines, and inflammation in a prospective study. In completing the proposed training and research plans, I will gain the necessary expertise to design, conduct, and analyze pharmacogenomics studies. This will allow me to compete effectively for future NIH support and propel me to an independent career in patient-oriented research.

Public Health Relevance

A toxicity of tacrolimus in kidney transplantation is the development of hyperglycemia and new onset diabetes after transplant, clinical conditions which increase the risk of cardiovascular events in these patients. Using genome-wide and candidate gene association studies, we will study the genetic factors associated with abnormal glucose metabolism in kidney transplant patients taking tacrolimus. This may allow modification of immunosuppressive treatment to decrease risk of diabetes and improve long term transplant outcomes.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23GM100183-03
Application #
8539384
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Long, Rochelle M
Project Start
2011-09-20
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
3
Fiscal Year
2013
Total Cost
$188,460
Indirect Cost
$13,960
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Stapleton, Caragh P; Birdwell, Kelly A; McKnight, Amy Jayne et al. (2018) Polygenic risk score as a determinant of risk of non-melanoma skin cancer in a European-descent renal transplant cohort. Am J Transplant :
Kensinger, Clark; Hernandez, Antonio; Bian, Aihua et al. (2017) Longitudinal assessment of cardiac morphology and function following kidney transplantation. Clin Transplant 31:
Birdwell, Kelly A; Chung, Cecilia P (2017) The Potential of Pharmacogenomics to Advance Kidney Disease Treatment. Clin J Am Soc Nephrol 12:1035-1037
Kensinger, Clark; Bian, Aihua; Fairchild, Meagan et al. (2016) Long term evolution of endothelial function during kidney transplantation. BMC Nephrol 17:160
Sanders, M Lee; Karnes, Jason H; Denny, Josh C et al. (2015) Clinical and Genetic Factors Associated with Cutaneous Squamous Cell Carcinoma in Kidney and Heart Transplant Recipients. Transplant Direct 1:
Birdwell, K A; Decker, B; Barbarino, J M et al. (2015) Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther 98:19-24
Oetjens, Matthew; Bush, William S; Birdwell, Kelly A et al. (2014) Utilization of an EMR-biorepository to identify the genetic predictors of calcineurin-inhibitor toxicity in heart transplant recipients. Pac Symp Biocomput :253-64
Birdwell, Kelly (2014) Role of pharmacogenomics in dialysis and transplantation. Curr Opin Nephrol Hypertens 23:570-7
Birdwell, Kelly A; Ikizler, Mine R; Wang, Li et al. (2012) Seasonal maintenance of influenza vaccine-induced antibody response in kidney transplant recipients. Am J Nephrol 36:201-7
Birdwell, Kelly A; Grady, Ben; Choi, Leena et al. (2012) The use of a DNA biobank linked to electronic medical records to characterize pharmacogenomic predictors of tacrolimus dose requirement in kidney transplant recipients. Pharmacogenet Genomics 22:32-42