Dendritic cells (DC) are the most potent antigen presenting cells (APC) and play a critical role in generation of immune responses against bacterial and viral pathogens, tumor antigens, and are involved in the development of autoimmune abnormalities. They belong to monocyte/macrophage myeloid lineage of cells and their function depends on the state of their differentiation and maturation. DCs are developed in bone marrow. However, the mechanisms governing DC differentiation in bone marrow microenvironment involving complex network of cytokines and cell-bound molecules remain largely unknown. We have accumulated data presented in this application demonstrating that DC differentiation is regulated by bone marrow stroma via cooperation between Notch and Wnt pathways. We propose a novel model of spatial regulation of DC differentiation in bone marrow and peripheral lymphoid tissues that is regulated by the nature of Notch ligands and the amount of Wnt produced by adjacent cells. Abnormal DC differentiation is one of hallmarks of immunological defects in cancer. It is considered as one of the major mechanisms of tumor escape. In preliminary experiments we have demonstrated that Notch and Wnt signaling in HPC from tumor-bearing mice is significantly inhibited. This was closely associated with inhibition of DC differentiation. We propose that down-regulation of these pathways could be responsible for abnormal DC differentiation in cancer. The overall goal of this proposal is to identify the mechanisms of these abnormalities and potential approaches to their correction. To achieve these goals we propose three specific aims:
Specific Aim 1. Investigation the role of Wnt signaling in DC differentiation and function Specific Aim 2. Study of cooperation between Notch and Wnt signaling in regulation of DC differentiation Specific Aim 3. Investigation the role of Wnt and Notch signaling in abnormal DC differentiation and function in cancer
Proposed research will investigate novel mechanism of regulation of DC differentiation in bone marrow microenvironment by Notch and Wnt signaling. We will test novel hypothesis that cooperation between Notch and Wnt pathways provides for spatial regulation of DC differentiation under physiological conditions and that defects in these pathways play a critical role in abnormal dendritic cell differentiation in cancer.
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