I have received combined training in internal medicine and basic biomedical research at Washington University, with the goal of becoming a physician-scientist and principal investigator conducting basic biomedical investigation in an interdisplinary research environment at a leading academic medical center. As a post-doctoral fellow, I am studying how indigenous gut microbes affect host biology. Using methods that allow germ-free (GF) normal and genetically manipulated mice to be treated with irradiation and bone marrow transplantation, I found that the microbiota influences sensitivity to radiation enteritis, a limiting factor for radiotherapy of abdominal and pelvic cancers. This proposal uses a series of novel gnotobiotic normal, knockout and chimeric mouse models to dissect the cellular and molecular pathways by which the microbiota modulates the radiosenstivity of intestinal endothelial and immune populations in the villus mesenchyme .
In specific aim 1, the microbial and host components of gut radiosensitivity will be determined, using gnotobiotic mice from specified genetic backgrounds colonized with defined collections of bacteria that receive defined doses of total body irradiation. Mice will be assessed by survival, histochemical, and immunohistochemical analyses, plus functional genomic studies of gene expression from laser capture microdissected villus epithelial and mesenchymal cell populations.
Aim 2 uses gnotobiotic transgenic/knockout and chimeric mice, plus recombinant protein, to elucidate the role of a gut epithelium-derived member of the angiopoietin family, Fiaf, in the Gl radioresponse.
Aim 3 employs 'radiation chimeras' (transplanting bone marrow from knockout mice into syngeneic normal or genetically engineered GF recipients) to further assess the cellular and molecular circuitry that shapes the radiosensitivity of the intestine - specifically focusing on the interaction between lymphocytes and endothelial cells. LAY SUMMARY: New research that illuminates novel features of the host-microbial relationship in the gut will be invaluable in developing directed therapies for radiation enteritis and other diseases that afflict the Gl tract. Furthermore, because of the central role for endothelial cell damage in a wide number of disease processes within the intestine and other organs, I expect to obtain insights about endothelial responses to injury that are applicable to the cardiovascular system where endothelial dysfunction plays a central role in disease pathogenesis.
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