Our published work includes a study of the intracellular domain of IL-7 receptor. This showed that the intracellular domain of other cytokine receptors can mimic some functions of the IL-7 receptor in T and B cell development. However one unique function of the IL-7 receptor is the induction of TCR gamma gene rearrangement. We also published our findings that pharmacological treatment with IL-7 induces a broad hematological stimulation, including myelopoiesis and erythropoiesis. This showed beneficial effects of IL-7 treatment beyond the expected effects on lymphopoiesis. We also published a study showing that signals from IL-7 receptor are required for development of T regulatory cells, and demonstrated that there is redundancy between the two ligands for IL-7R alpha TSLP and IL-7 itself. Although IL-7 is essential for normal T cell development and maintenance, it has not been determined which cells actually produce the IL-7 protein because it is below the level of detection by immunohistochemistry. We produced mice with a marker knocked into the IL-7 locus that permitted visualizing the producing cells. This showed an extensive reticular network of IL-7-containing processes in thymus and bone marrow and the study is submitted for publication. We produced a new antibody against the essential phosphotyrosine motif in the intracellular domain of IL-7 receptor; we expected this motif to be phosphorylated after IL-7 stimulation but instead made the unanticipated observation that the site is constitutively phosphorylated and bound to Stat5 this is submitted for publication. We performed an extensive study of the roles of the death protein Bim and its counterpart, the pro-survival protein Mcl-1. We show that these are regulated post-translationally by IL-7 and aim to define the mechanisms using an exciting new approach. IL-7 protects Mcl-1 from degradation and we have visualized this with Mcl-1-GFP. We are screening the whole expressed genome of shRNAs in lentivirus to identify components of this mechanism. Enthusiasm about this approach led us to submit a proposal, which was accepted by the SBIR, to offer a contract to array the entire human and mouse shRNA expressed genomes. This robotic screening method will be used by NCI to identify new pathways in cancer cells. The new Cancer Inflammation Program has inspired two new projects in colon cancer. We are developing knockin reporter mice for two IL-17 genes using two colors. This will enable us to visualize cells producing these critical inflammatory cytokines during bowel inflammation leading to colon cancer. We are also developing suppressive cytokines to treat bowel inflammation and colon carcinogenesis. These include IL-17 and IL-35 delivered in the oral bacterium Lactococcus lactis.
Showing the most recent 10 out of 19 publications
