Patients with inflammatory bowel disease (IBD) are known to be at increased risk for intestinal and colorectal cancer. Mechanisms of this inflammation to cancer sequence have since been extensively characterized. Less characterized, however, are the mechanisms involved in the development of extraintestinal manifestations of disease, including hematopoietic cancers such as non-Hodgkin's T-cell lymphomas, hepatobiliary cancers, and other solid cancers and autoimmune disorders. We have previously identified genotoxicity to peripheral leukocytes in mice with chronic intestinal inflammation. Systemic genotoxicity is there an important and previously unappreciated consequence of chronic intestinal inflammation, which over time may promote the development of extraintestinal disease. In this application, we propose to determine the long-term implications of and determine the mechanisms involved in intestinal inflammation-associated systemic DNA damage.
The first aim will clarify genotoxic load to multiple cell types in lymphoid and non-lymphoid tissues during chronic intestinal inflammation, and then characterize the long-term pathological effects these may impose.
Our second aim i s a mechanistic aim in which we will determine the sufficiency of cytokines such as TNF-1 and IL-12 in inducing systemic genotoxicity in vivo and in inducing genotoxicity in vitro, and then identify potential signaling pathways downstream of the receptors involved in induction of intracellular RONS formation. Necessity of de novo protein synthesis post-cytokine treatment and the temporal scheme of intracellular ROS and DNA damage will be determined via imaging analysis and treatment with ROS scavengers. In our third and fourth aims, we will test the hypothesis that damaged leukocytes from the gut circulate into the periphery, and the hypothesis that a local inflammatory response in various distant tissues are responsible for systemic genotoxicity, respectively. Specific components of the inflammatory response in distant tissues that may be responsible for this effect will be tested via adoptive transfer of serum or leukocyte populations from Ly5.1 mice with chronic intestinal inflammation into congenic Ly5.2 mice, and testing for systemic genotoxicity in Ly5.2 cells. Together, these experiments should clarify the inflammatory mediators and target cell types that link intestinal inflammation with systemic genotoxicity.
This project is highly relevant to patients with long-term chronic intestinal inflammation, such as IBD, who may develop extraintestinal manifestations of disease in addition to increased risk for intestinal cancers. The successful completion of the aims proposed will allow for determination of mechanisms involved in a novel effect previously not described in IBD patients, which we believe promotes development of these extraintestinal manifestations including lymphomas. This work will also lead to identification of targets that may be used for treatment and prevention of these manifestations due to persistent systemic genotoxicity.
|Yamamoto, Mitsuko L; Schiestl, Robert H (2014) Intestinal microbiome and lymphoma development. Cancer J 20:190-4|
|Chapmana, Aaron M; Malkin, Daniel J; Camacho, Jessica et al. (2014) IL-13 overexpression in mouse lungs triggers systemic genotoxicity in peripheral blood. Mutat Res 769:100-7|
|Yamamoto, Mitsuko L; Chapman, Aaron M; Schiestl, Robert H (2013) Effects of side-stream tobacco smoke and smoke extract on glutathione- and oxidative DNA damage repair-deficient mice and blood cells. Mutat Res 749:58-65|