Cell and tissue injury are accompanied by responses that serve to limit further damage and initiate processes requisite to repair and restoration of normal structure and function. These include both inflammation as well as cellular stress. These events are, however;also recognized as important contributing features of tumorigenesis though the pathways involved remain poorly understood. Initiation of inflammatory response through stimulation of pattern recognition receptors leads to the production of pro-inflammatory cytokines, which further amplify inflammatory gene expression in multiple target cell populations. Cell stress responses can modify inflammation and contribute significantly to cell and tissue repair. The downstream signals associated with both inflammatory and stress responses lead to altered patterns of transcription factor activation/function, post-transcriptional regulation and target gene expression. Collectively these changes translate into the loss of control of normal cellular proliferation, migration, and neighboring cell-cell interactions and ultimately contribute to the malignant transition. This program will address aspects of pathogen-initiated signaling pathways focusing upon TLRs, stress responses integrated by translational control through elF2a phosphorylation, transcriptional and post-transcriptional control mechanisms, and the causal links between inflammatory signaling and neoplasia. Project 1 is designed to dissect multiple pathways associated with the action of TLR3 and associated factors (TRIF and IRF3) and their control of inflammation linked tumorigenesis. Project 2 is focused upon how nuclear lysine methylation of STATs 1 and 3 and NFkB at the promoter site provides gene-specific inflammatory responses to diverse external signals. Project 3 will assess novel post-transcriptional mechanisms through which cell stress regulates expression of the TIS7/IFRD1 gene and how the distinct cell type specific functions of this gene may influence stress/inflammation driven colon tumor development. Finally Project 4 is to investigate how SIGIRR, a negative regulator for TLR-IL-1R signaling, modulates inflammation-induced tumorigenesis in the colon through its impact on commensal microflora-dependent homeostasis and innate and adaptive immune responses of the colonic epithelium.
The overall objective of the proposals that comprise this Program Project application is to define cellular and molecular mechanisms through which response to chronic injury and inflammation promote the development of cancer. The primary goal is to investigate locus-specific and cell type-specific responses to provide insight into how inflammatory signals are read by different cells and in different situations, thus helping to explain why certain tumorigenic stimuli affect only a limited number of specific cells. The results of the proposed work will contribute significantly to understanding the fundamental processes that enable and promote the development of cancer and how these are influenced by the inflammatory status of the individual.
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