Production of inflammatory cytokines and interferons by innate immune cells, within the tumormicroenvironment, is a major determinant of tumor progression. Damage-associated molecular pattern(DAMP) recognizing receptors in myeloid cells are activated by ligands generated by the tumor cells, cytokinesare induced locally and act upon the tumor cells to promote or impair their proliferation. Recent literaturesuggests that DNA and RNA are the major mediators of communication between the tumor cells and the innateimmune cells. Our interests are in analyzing the biochemical pathways of signaling elicited by specific nucleicacid receptors in myeloid cells and investigating the effects of their manipulations in mouse models, which willbe greatly facilitated by the newly generated TLR3, TLR9 and EGFR conditional knock-out mouse lines. Wewill test the hypothesis that the protein tyrosine kinase (PTK) activity of the epidermal growth factor receptor(EGFR) is essential for signaling by the two endosomal Toll-like receptors, TLR3 and TLR9, and by STING, theER-bound mediator of cytoplasmic DNA signaling. Specifically, we will investigate the roles of EGFR and Src inTLR3 and TLR9 signaling by determining the biochemical requirements for TLR, EGFR and Src interactions toelicit signals. We will also identify the specific functions of EGFR and the adaptor protein, TRIF, in mediatingSTING-signaling and their contributions to STING-mediated protection from viral pathogenesis in mice will beevaluated. Finally, we will evaluate the role of EGFR-mediated cytokine production by myeloid cells inregulating tumor growth in three murine model systems: chemically induced skin and colon cancers andtransplanted glioma. The above studies will illuminate the different mechanisms by which EGFR promotessignaling by three intracellular nucleic acid DAMP- recognizing receptors and thereby affects tumor growth.
Because inflammation and cancer progression are closely connected; it is important to understand howimmune cells present in the tumor microenvironment impact the disease process. This proposal is focused ondetermining the role of the epidermal growth factor receptor; a protein tyrosine kinase; in regulating thefunctions of three intracellular pattern recognition receptors that recognize nucleic acids released from dead ordamaged cancer cells. We will examine the effects on tumor progression in mice in which these receptors arenon-functional only in the immune cells.
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