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Kevin Gardner, M.D., Ph.D.

Laboratory of Receptor Biology and Gene Expression Head, T Cell Transcription Regulation Group Investigator 41 Library Dr Room D804B Bethesda, MD 20892 Phone:   301-496-1055 Fax:   301-496-4951 E-Mail:   kevgar@helix.nih.gov

Biography

Dr. Gardner received his B.S. from Yale University and earned his M.D. and Ph.D. from the Johns Hopkins University School of Medicine where he studied the regulation of membrane skeletal proteins in the Department of Cellular Biology and Anatomy. He completed residency training in anatomic pathology at the National Cancer Institute and is board certified in Anatomic Pathology. Dr. Gardner has had a long term interest in the cellular and molecular biology of gene regulation and, while at NIH, has been developing strategies to define pathways and mechanisms of transcriptional control in activated T-cells. Dr. Gardner is a member of the editorial boards of the American Journal of Pathology the International Journal of Medical Sciences, and the Open Clinical Chemistry Journal. He is an elected member of the American Society for Clinical Investigation, and was a recipient of an NIH Director's award in 2007.

Research

My laboratory applies functional genomic approaches to understanding how molecular signaling events are integrated in the nucleus to influence gene expression. The primary focus of the work is to determine the mechanism through which gene regulatory sequence composition and structure are deciphered at the molecular level to dictate how mammalian cells modulate their transcriptional activity in response to changes in their environment and how such mechanisms are deranged or reconfigured in cancer. This effort employs a multidisciplinary approach that integrates the use of bioinformatics, multivariate computational analysis and high throughput cell-based assays to study mechanisms of stimulus-evoked transcriptional regulation in activated human T-cells and multiple myeloma. Using this approach we are beginning to develop a perspective not only on the inherent language or logic of gene regulatory composition, but we are developing conceptual frameworks that will serve to explain how population variation in such genomic sequences can contribute to disease susceptibility and differential response to therapeutic intervention. Consequently, the insights developed from this approach have led to the initiation of several translational components of the work designed to discover innovative molecular targets for therapeutic modulation of immune cell proliferation and function, and has initiated a new focus on the molecular and cellular biology of multiple myeloma. In addition, several collaborative interactions have grown from the approaches in the lab designed to aid other investigators in defining the trends and pathways of transcriptional regulation in an angiogenesis model and a study of the changes in the transcriptional regulatory circuitry of chronic lymphocytic leukemia before and after chemotherapy. The work and progress in the laboratory can be divided in to 3 interconnected approaches using T-cell activation and/or the transcriptional and molecular signaling biology of multiple myeloma as models systems: 1.) Profiling of transcriptional targets; 2.) Kinetic profiling of transcriptional factor occupancy in vivo; and 3.) Characterization of hierarchical transcriptional complex assembly at short and long range chromatin regions of the Interleukin 2 (IL-2) and other gene loci.

Profiling of transcriptional targets. Profiling of transcriptional targets (PTT) uses high throughput transcriptional assays to assess transcriptional regulation under multiple conditions, then applies multivariate analysis to discern mechanisms of transcriptional control from the trends and patterns in the high dimensional data. Using T-lymphocytes and the process of T-cell activation as a model system, we have profiled patterns in transcriptional regulation that reflect the composition and arrangement of the regulatory sequences at targeted genes. This method has also become a powerful analytical tool to define the biological activity of many different compounds under investigation in clinical studies including thalidomide analogues and histone deacetylase inhibitors.

Kinetic profiling of transcription factor occupancy in vivo. We have been using the chromatin immuno-precipitation assay to generate kinetic profiles of the association and occupancy of nuclear factors at target genes during T-cell activation. We have found that specific kinetic profiles of p300 occupancy at target genes can be used in a 'reverse genomics' approach to identify classes of genes that share a common promoter composition and structure. Moreover this promoter similarity can be used to identify other genes that share the same properties of p300 recruitment and regulation by histone deacetylase inhibition. To facilitate analysis on a genomic scale, we have successfully adapted the chromatin immuno-precipitation assay for high throughput analysis using a micro-array platform where 100's to thousands of specific protein-DNA interactions can be simultaneously assessed.

Characterization of hierarchical complex assembly at short and long range chromatin regions of the Interleukin 2 (IL-2) and other gene loci. Using the IL-2 promoter as a model system, we have found that, during T-cell activation, there is an ordered recruitment of DNA binding transcription factors and p300 to the proximal promoter of the IL-2 gene. Ongoing research is aimed at characterizing any additional p300 associated complexes along the 8 KB 5' regulatory loci of the IL-2 gene that confers lineage specific mitogen inducibility. Paradigms developed through this approach will be used to define the long range regulatory role of p300 in other cellular systems with particular emphasis on those genes that have roles in the etiology and progression of multiple myeloma.

This page was last updated on 10/8/2008.