Z01 BC 009287 (Z01) | |||
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Title | Cytokines and T Cell Development | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Durum, Scott | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $780,768 | Project Dates | 10/01/1984 - N/A |
Fiscal Year | 2008 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Autoimmune Diseases (10.0%) Cancer (100.0%) Digestive Diseases (20.0%) Inflammatory Bowel Disease (20.0%) |
Colon/Rectum (20.0%) Leukemia (100.0%) Lymphoma (50.0%) Non Hodgkins Lymphoma (50.0%) |
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Research Type | |||
Normal Functioning Vaccines |
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Abstract | |||
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. In collaboration with Rockland Inc., we produced a new antibody that is yielding new insights into signaling from the IL-7 receptor. This rabbit antibody reacts with the essential phosphotyrosine motif in the intracellular domain of IL-7 receptor. The prevailing model of signaling predicted that this motif would be phosphorylated after IL-7 stimulation, thereby attracting Stat5. However, we made the unanticipated observation that the site is constitutively phosphorylated and constitutively bound to Stat5. IL-7 stimulation therefore induces phosphorylation of Stat5, but not the IL-7 receptor as expected. This study 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 IL-7 regulates these proteins post-translationally 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. This shRNA approach is an extremely powerful discovery tool in cancer research. To apply it to other systems in cancer cells, we submitted a proposal to the SBIR to offer a contract to array the entire human and mouse shRNA expressed genomes. The proposal was approved and 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 that diverge from our previous focus on IL-7. One project involves IL-17, a T cell cytokine that strongly promotes the intestinal inflammation leading to colon cancer. It has not been determined where IL-17 is produced during this inflammatory response. 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. A second project aims to inhibit the bowel inflammation leading to colon cancer. IL-27 and IL-35 are suppressive cytokines that we aim to deliver to the bowel using an engineered oral bacterium, Lactococcus lactis. |