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.
This proposal is intended to better understand how genetic variation contributes to individual sensitivity to GCs. The long term goal is to identify patients, using their genetic make up, that are at risk for toxicities and non- response associated with GCs with the intent to reduce their chances of an adverse event and improve their care.
|Wu, Kehua; Gamazon, Eric R; Im, Hae Kyung et al. (2014) Genome-wide interrogation of longitudinal FEV1 in children with asthma. Am J Respir Crit Care Med 190:619-27|
|Grassi, Michael A; Rao, Vidhya; Winkler, Kathryn P et al. (2014) Genetic variation is the major determinant of individual differences in leukocyte endothelial adhesion. PLoS One 9:e87883|
|LaCroix, Bonnie; Gamazon, Eric R; Lenkala, Divya et al. (2014) Integrative analyses of genetic variation, epigenetic regulation, and the transcriptome to elucidate the biology of platinum sensitivity. BMC Genomics 15:292|
|Weng, Liming; Ziliak, Dana; Lacroix, Bonnie et al. (2014) Integrative "omic" analysis for tamoxifen sensitivity through cell based models. PLoS One 9:e93420|
|Geeleher, Paul; Cox, Nancy J; Huang, R Stephanie (2014) Clinical drug response can be predicted using baseline gene expression levels and in vitro drug sensitivity in cell lines. Genome Biol 15:R47|
|Lenkala, Divya; LaCroix, Bonnie; Gamazon, Eric R et al. (2014) The impact of microRNA expression on cellular proliferation. Hum Genet 133:931-8|
|Geeleher, Paul; Cox, Nancy; Huang, R Stephanie (2014) pRRophetic: an R package for prediction of clinical chemotherapeutic response from tumor gene expression levels. PLoS One 9:e107468|
|Weng, L; Ziliak, D; Im, H K et al. (2013) Genome-wide discovery of genetic variants affecting tamoxifen sensitivity and their clinical and functional validation. Ann Oncol 24:1867-73|
|Wheeler, H E; Gamazon, E R; Stark, A L et al. (2013) Genome-wide meta-analysis identifies variants associated with platinating agent susceptibility across populations. Pharmacogenomics J 13:35-43|
|Weng, Liming; Zhang, Li; Peng, Yan et al. (2013) Pharmacogenetics and pharmacogenomics: a bridge to individualized cancer therapy. Pharmacogenomics 14:315-24|
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