Developed laboratory procedures for handling a variety of sample types including neutrophils, peripheral blood mononuclear cells, T-lymphocytes, whole blood bronchoalveolar lavage, spleen, liver, lung, and heart.? ? Tested and validated amplication procedures for handling small samples.? ? Gained experience with oligonucleotide microarrays for several species including human, monkey, mouse and rat.? ? Data analysis pipeline was developed and extensively tested that includes variance stabilized normalization, gene selection and thematic analysis procedures.? ? NIH Bioinformatics Cooperative (http://affylims.cit.nih.gov/) was established with development and dissemination of the MSCL toolbox and construction of a database containing over 3700 microarrays.? ? Founded the NIH sponsored Symposium on the Functional Genomics of Critical Illness and Injury focused on knowledge emerging from functional genomic databases relevant to critical care medicine. The fourth meeting (November, 2006) was attended by over 400 participants from 10 countries and provided a forum for the presentation of cutting edge research applying high throughput biotechnologies to the study of critical illness and injury (www.strategicresults.com/fg4/). ? ? Investigated interactions between interferon-alpha (IFN-alpha) and dexamethasone in primary bronchial epithelial cells. Dexamethasone triggered a specific transrepression of IFN-alpha-induced responses and had a substantially greater effect on gene expression in the presence that in the absence of IFN-alpha.? ? Global transcriptional analysis of circulating leukocytes highlighted the intense oxidant and inflammatory nature of steady-state sickle cell disease and provided insight into the broad compensatory responses to vascular injury (Blood, 2004). Circulatory stress in sickle cell disease was also associated with gene expression changes in platelets that were associated with abnormalities of arginine metabolism (Circulation, 2007).? ? The administration of a single dose of intravenous endotoxin to humans led to a rich profile of gene expression changes in blood. These included the induction of genes associated with pattern recognition molecules, intracellular signaling and transcription, cell mobility, and defense function. T lymphocyte-associated genes were repressed, and many genes not previously associated with endotoxin-induced inflammation were differentially regulated during this response. Notably, these alterations in gene expression were rapidly extinguished within 24 h.? ? Gene expression profiling was used to globally identify numerous genes regulated by NO. This work has led to the discovery of new signal transduction pathways and regulatory mechanisms by which NO influences gene expression (BMC Genomics, 2005; Nuc Acid Res 2006; J Biol Chem, 2006). These transcriptomic effects of NO were associated with its ability to regulate inflammation and cell proliferation in the vasculature.? ? The genetic basis of an undifferentiated case of human autoimmune lymphoproliferative syndrome (ALPS) was uncovered using expression profiling (PNAS, 2007). A germline activating mutation in NRAS was discovered as the underlying cause. This finding suggests that RAS-inactivating drugs, such as farnesyltransferase inhibitors might be therapeutically useful in human autoimmune disorders.
Showing the most recent 10 out of 13 publications
