Genome-wide interrogation of genetic signatures for glucocorticoid sensitivity

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DESCRIPTION (provided by applicant): The principle investigator's career goal is to be a successful translational researcher in the field of Clinical Pharmacology. With this Award, she plans to further her training in systems biology, statistical genetics and bioinformatics. She proposes to extend a genome-wide model developed during her fellowship to broader therapeutic application beyond chemotherapy and validate her findings in patient samples. The PI's long-term goal is to combine her patient care knowledge from Pharmacy school and research knowledge through her work in Pharmacogenetics to eventually improve the quality of life for patients. Dr. Eileen Dolan (Internationally recognized researcher in pharmacogenomics) will serve as the PI's main mentor; while Drs. Nancy Cox (internationally recognized statistical geneticist) and Mark Ratain (internationally recognized leader in pharmacogenetics and phase I trial design) will co-mentor the PI's scientific and career development. Her advisory committee consists of Drs. Scott Weiss, Julian Solway and Kelan Tantisira, who will provide scientific guidance in utilizing patient samples in studying pharmacogenomics markers for glucocorticoid (GC) sensitivity in asthma. An objective of this proposal is to take a concerted translational effort to elucidate the underlying cause for the inter-individual differences in sensitivity to GCs, one of the most commonly used agents in treating inflammatory diseases such as asthma, inflammatory bowel disease and arthritis. Our hypothesis is that a novel genome-wide model developed using International HapMap lymphoblastoid cell lines (LCLs) are suitable in identification of genetic polymorphisms as predictors of cellular sensitivity to GCs. Our specific aims are 1) To develop and refine GC sensitivity phenotypic assays to quantify in vitro GC response and toxicity; 2) To identify genetic polymorphisms that are associated with GC susceptibility phenotypes through gene expression; 3) To validate candidate genetic variants/genes in patient samples. Our long-term goal is to predict patients "at risk" for adverse events and/or non-response prior to administration of GCs.