In spite of significant efforts and progress over the last decade, the genetic determinism of arthritis remains poorly understood, and there is a need for continued effort for the genetic dissection of arthritogenesis in models, with approaches that allow a global perspective of genetic interactions. The present project aims to exploit the potential offered by outbred mice. We propose to analyze the susceptibility to arthritis in """"""""Heterogenous Stock"""""""" (HS) mice, generated from a group of founder inbred strains by serial intercrossing for more than 50 generations. The accumulated recombination events turn each HS chromosome into a fine-grained mosaic of the founder strain genomes, with a potential for QTP mapping at high precision. These will be tested by transfer of arthritogenic serum from K/BxN arthritic mice, a model is well suited for a genetic dissection in HS mice because it is robust and reproducible, and does not depend on a particular genetic background. This will address the many players in the effector phase of the disease process (mast cells, neutrophils, synoviocytes, complement, FcR, inflammatory cytokines, lipid mediators). A key aspect of the project is that it will """"""""piggy-back"""""""", at a fraction of the cost of a de novo program, on a 2000 animals, 6000 SNP analysis of HS mice for loci controlling behavioral and metabolic traits supported by the Welcome Trust at Oxford. By testing in the K/BxN arthritis model the siblings of fully-genotyped animals from the behavioral genetics project, it will be possible to derive highly detailed genetic maps from low density/cost genotyping. This project is a collaborative endeavor between the Mathis/Benoist lab at the Joslin Diabetes Center, Boston and the Wellcome Trust Center for Human Genetics, Oxford, UK. Each group brings a unique[ expertise in autoimmunity (Boston) and genetics (Oxford).
