This K23 proposal will assist the candidate to achieve her long-term career goal of becoming an independent academic researcher in the field of clinical pharmacology with a primary focus in pharmacogenetics. The immediate steps to reach this goal include obtaining additional training in genetics, establishing a comprehensive mentorship plan that will guide her career development, and the performance of an innovative research project designed to provide hands-on training in the skills the candidate needs to develop to facilitate her transition to independence. Thus, this K23 proposal has three major components: First, the candidate, an individual who has Doctor of Medicine and Master of Public Health degrees and has made serious commitments to an academic career in patient-oriented research but lacks skills in genetics. Second, a career development plan designed to provide the candidate with mentoring and critical skills in areas new to her but necessary for her development: genetic epidemiology, bioinformatics and advanced statistics. Third, a research project that integrates rigorous training and mentored research to address an important scientific question: What are the genetic mechanisms underlying variability in the efficacy and toxicity of glucocorticoids (GCs)? GCs are potent anti-inflammatory and immunosuppressant drugs used to treat common illnesses, including several life- and organ-threatening diseases. Despite their frequent use, there is large variability in efficacy and toxicity that results in inadequate therapeutic responses and GC-induced metabolic side effects. The large inter-individual variability in GC response has a genetic component, but the genetic determinants of this variability remain unknown. This proposed research would define the genetic contributions to variability in GC efficacy and toxicity using two relevant GC-related phenotypes: GC-induced lymphopenia (a well- established, validated pharmacodynamic measure of GC effect) and GC-induced glucose intolerance (an important side effect of GC therapy). Thus, we propose three Specific Aims: 1) identify the genetic determinants of GC efficacy using GC-induced lymphopenia as a phenotype using a genome-wide approach; 2) determine the combined effects of genetic variants known to be associated with glucose homeostasis on the risk of GC-induced glucose intolerance; and 3) validate the genetic variants associated with GC-induced lymphopenia and glucose intolerance using GC-evoked responses in healthy subjects. For the first two specific aims we will use Vanderbilt's DNA bank (BioVU) the largest clinical practice-based biobank linked to de- identified copies of electronic medical records.
In aim 3 we will minimize the effects of confounders in GC response by studying these phenotypes in a well-controlled environment by challenging healthy individuals with a single dose of GC. The candidate's development is nurtured through a supportive environment at Vanderbilt University, which has unique resources to perform in silico and in vivo human pharmacology and pharmacogenetic studies. Her mentors, Dr. Michael Stein and Dr. Nancy Cox, are well-established senior investigators with longstanding NIH funding and outstanding expertise in clinical pharmacology and pharmacogenetics. They strongly support the candidate's career plan and have committed time and resources to train and assist her. This, along with the strengths of the proposed training program and project, will ensure the candidate's success in becoming an independent academic researcher.
Glucocorticoids are organ-sparing and life-saving drugs that are prescribed for several conditions. However, there is large variability in their efficacy and toxicity that results in therapy failure and adverse events. Characterization of the genetic factor that are involved in the variability of glucocorticoid response have the potential to reveal unknown mechanisms that can be target pharmacologically to improve the care of millions of patient that use this medication and reduce the occurrence of unwanted side-effects.
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| Kawai, Vivian K; Levinson, Rebecca T; Adefurin, Abiodun et al. (2017) Variation in the ?2A-adrenergic receptor gene and risk of gestational diabetes. Pharmacogenomics 18:1381-1386 |
| Adefurin, Abiodun; Darghosian, Leon; Okafor, Chimalum et al. (2016) Alpha2A adrenergic receptor genetic variation contributes to hyperglycemia after myocardial infarction. Int J Cardiol 215:482-6 |
| Iwuchukwu, Otito F; Ramirez, Andrea H; Shi, Yaping et al. (2016) Genetic determinants of variability in warfarin response after the dose-titration phase. Pharmacogenet Genomics 26:510-516 |
