We previously cloned a G protein coupled receptor termed OGR1 from cancer cells and generated OGR1 knockout mice (ogr1-/-). Our substantial preliminary data suggest that OGR1 plays crucial roles in immune cells, and in T cells and Gr1 and CD11b double positive (DP+) cells in particular. We hypothesize that OGR1 expression not only affects the numbers of DP+ cells, but also their functions after prostate cancer (PCa) tumor cell challenge;and DP+ cells are the major suppressor cells and T cells are the major effector cells for OGR1-depedent effects in PCa. These concepts will be tested in three Specific Aims. The main goal of this proposal is to determine the cellular and molecular mechanisms underlying the functions of OGR1 in immune cells pertinent to its role in PCa tumorigenesis and metastasis.
Aim 1. Investigate the role of OGR1 in T cells in PCa tumorigenesis and metastasis by 1) determining the functions of OGR1 in T cells in vivo using T cells depletion and adoptive transfer mice;by 2) examining the effect of OGR1 depletion in specific T cell lineages using specific Cre-Lox systems in mice;and by 3) determining the time course of T cell infiltration and tumor cell eradication in ogr1-/- mice.
Aim 2. Determine the role of OGR1 in Gr1 and CD11b double positive (DP+) cells in PCa tumorigenesis and metastasis by 1) determining OGR1 expression in which immune cell populations is functionally involved and required for tumor development;by 2) determining the role of OGR1 in myeloid lineage in PCa development using LysM Cre-mice;and by 3) testing whether the OGR1 effects on tumorigenesis and DP+ cells are restricted to certain cancer cells.
Aim 3. Delineate molecular mechanisms underlying OGR1's role in T and DP+ cells. 1) Investigate the signaling mechanisms by which OGR1 regulates the arginase activity in DP+ cells. 2) Elucidate the mechanisms by which the TRAMP-C2 conditioned medium and/or TGF-beta1 induce up-regulation of OGR1 in immune cells. 3) Test the effects of OGR1-specific agonists/antagonists in immune cells and in vivo. 4) Determine the structural requirement in OGR1 for its functions. Our long-term goal is to develop OGR1-based novel immunotherapy for cancers.
We have found that lack of expression of a gene called OGR1 in T cells (the major defensive cell type to against cancer) and Gr1 and CD11b positive cells (DP+ cells) greatly reduce the chance for prostate cancer (PCa) development in mouse models. We will determine the novel functions and mechanisms of OGR1 in these cells, which will lay a crucial base for developing new treatment regiments for PCa.
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