The SLRPs form a family of structurally related extracellular matrix proteoglycans/glycoproteins that are expressed in vertebrae but not in Drosphila and C. elegans. The SLRPs appear to in vivo function primarily as adaptor proteins regulating the assembly the assembly of collagen fibers as revealed by detailed analyses of several mouse lines deficient in individual SLRPs. We now propose to continue our studies on the role of SLRPs in skeletal biology. We will examine the importance of propeptides and Zn2+ binding on the interactions and multimer structures of SLRPs using a variety of biochemical analyses. Furthermore, we will characterize in submolecular detail, the interactions of SLRPs with different types of collagens. In these studies, we will use recombinant SLRPs and collagen-like synthetic peptides and recombinants expressed in bacteria. We will continue our analyses of mice deficient in epiphycan and osteoglycin focusing on our recent observation that epn-/- mice develop Osteoarthritis at an early age. We will characterize this mouse model of Osteoarthritis using a global transcriptional analysis as well as to seek to rescue the phenotype by expressing selected SLRPs as transgenes behind the Col2al promoter. Finally, we will characterize a newly discovered SLRP-like orphan receptor that contains a putative transmembrane segment and may represent a novel type of collagen receptor. These studies will be carried out using biochemical and cell biological techniques combined with in vivo studies.
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