TRANSCRIPTOME 2002: From Functional Genomics to Systems
The Hypoxic Macrophage Transcriptome Profile: A Strategy to Increase the Discovery of Biologically Relevant and Novel Targets for Angiogenesis and Inflammation
Jonathan R. White, Robert A. Harris, Marie H. Craigon, Georgina L. Beard, Sheena R. Lee, Stuart M. Naylor, Chris R. Mundy, Oxford BioMedica (U.K.) Ltd, Medawar Centre, Oxford Science Park, Oxford, UNITED KINGDOM
Macrophage infiltration at sites of hypoxia is found in several human diseases, including cancer, rheumatoid arthritis and atherosclerosis. The macrophage has been shown to play roles in disease initiation, progression and treatment. Since hypoxia modulates important macrophage functions, we have investigated the transcriptional response to hypoxia. We have used a strategy to increase the sensitivity and biological relevance of conventional gene array approaches. To increase sensitivity, the key transcription factors involved in the hypoxia response were over-expressed in primary human macrophages, using viral vectors, together with the exposure of cells to hypoxia. RNA samples were subjected to gene array analysis, using non-biased arrays representing the majority of the human transcriptome. From this data, a focused secondary array was produced, also including a panel of indicator genes of macrophage function. The secondary array was used to increase the biological meaning of the original findings. Firstly an extensive panel of samples examining other stimuli frequently occurring with hypoxia in specific diseases were tested. Cells treated with a panel of cytokines were also used to help elucidate inflammatory functions of the arrayed hypoxia regulated genes. As final validation, clinical material was applied to the array. Following in depth analysis of the whole data set, potential novel disease targets are being selected for validation using primary human cells.
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