Cells of the myeloid lineage are the major cellular component of the innate immune system. They orchestrate the adaptive immune response and play a major role in inflammatory pathologies and tumour progression. Given these facts, a more thorough understanding of the control of myeloid cell function is clearly warranted.
Our proposal aims to address this problem directly, by investigating a newly identified family of myeloid receptors. This family is orthologous to a previously identified human receptor, CMRF-35A, and we have thus named them CMRF-35 like molecules (CLM). CLMs are expressed predominantly by myeloid cells.
Our initial studies have been focused on one receptor, CLM-1 and suggest that CLM-1 can block osteoclastogenesis at an intermediate stage of differentiation. Because of the evident and implied importance of this receptor family in the regulation of myeloid cells, I am interested in pursuing studies of their function.
The studies will be focussed in the following areas:
- Complete definition of the CLM receptor family. Initial studies will focus on a more thorough definition of the receptor family in terms of cell and tissue expression.
- Signal transduction studies. We will first attempt to define proteins associating with select CL M receptors, and will use cytoplasmic domain mutants to further delineate signalling pathways engaged by these receptors.
- Ligand identification. A key to determining receptor function is identification of the receptor ligands. This is a particularly challenging task, and to increase chance of success we will use a number of novel library-based approaches.
- Functional studies. Even prior to ligand identification, we will use monoclonal antibodies to initiate functional studies of the CLMs. These will be influenced by cell expression, but they are likely to include typical myeloid cell assays.
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