Cadherin-11-cre deleter mouse

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ABSTRACT The objective of this grant application is to validate a novel mouse model enabling gene deletion in arthritogenic fibroblast-like synoviocytes (FLS). FLS are local joint-lining non hematopoietic cells that significantly contribute to joint and bone damage in active rheumatoid arthritis. This cell type is considered as a promising target for novel therapies to enhance control of disease activity and/or spare immunosuppression in patients with rheumatoid arthritis. However, the lack of a deleter mouse strain able to induce gene deletion specifically in FLS and their key subpopulations has been a serious limitation to both our understanding of the mechanism of action of this cell type in RA, and to the validation of novel targets for FLS-directed therapies. To begin addressing this bottleneck in the field, we have generated a novel deleter mouse strain that for the first time enables gene deletions specifically driven by the promoter of cadherin-11, a molecule that marks an aggressive population of FLS both in arthritic mice and humans with rheumatoid arthritis. In Aim 1 we will provide evidence that our new cre deleter strain is expressed selectively in FLS and throughout the course of experimental arthritis. In Aim 2 we will provide proof of principle evidence that cre expression in FLS does not influence severity of disease and that the new strain is able to drive FLS-specific deletion of a test gene believed to operate in arthritis via an action on FLS. Our goal is to generate an important shared resource for everybody working in the FLS field. Thus, if the studies funded by this grant succeed, we are firmly committed to depositing the model at JAX even before publication, as soon as sufficient data are collected to support use of such a needed resource by the whole RA research community.