Wellcome Trust PhD Programme for Clinicians at the University of Edinburgh: 'Comparative genomics of the inflammatory response'. (360G-Wellcome-090385_Z_09_Z)

Sepsis accounts for over 200,000 deaths each year in the USA alone. Death from sepsis is a consequence of diffuse activation of the innate immune system. This process is controlled by transcriptional regulation within the cells of the innate immune system. A limiting factor in attempts to identify the key genes that direct this process is the limited variability within the human population. I intend to fully exploit the diversity of mammalian biology by applying comparative transcriptomics to this problem. Due to the evolutionary pressure applied to the key regulators of innate immunity, many of these regulators are likely to differ between species, and will be polymorphic within species. There is a further reason to expect that important differences exist: mice are approximately 100-fold less sensitive to LPS in vivo than humans. By comparing the transcription response to lipopolysaccharide of macrophages from mice and humans, I aim to: 1. Identify differentially-expressed LPS-responsive regulatory elements; 2. Use this knowledge to modify the LPS response of cultured macrophages; in order to, 3. Find novel therapeutic targets for modification of the innate immune response.