Muscle is critically dependent on proper interactions with the extracellular matrix for force transmission, signal transduction, and the maintenance of membrane integrity. Failure of this system can cause muscular dystrophy. The muscular dystrophies are genetic diseases characterized by an ongoing breakdown of muscle, often leading to considerable disability and premature death. The aim of my laboratory is to untangle the interplay between muscle and the extracellular matrix, not only to understand its basic biology, but also its relevance for the pathogenesis of muscular dystrophies. Taking leads from disease related observations we approach this interface both from the cell membrane and the extracellular matrix using morphological, biochemical, and genetic techniques. Dystrophin is the protein deficient in Duchenne muscular dystrophy. It is associated with a group of proteins, some of which span the membrane. This protein complex appears to be part of a link to the extracellular matrix. The sarcoglycan complex is part of the dystrophin-associated proteins and is mutated in four forms of muscular dystrophy. However, extracelluar ligands for this complex are not yet known so that its normal functions have remained unclear. Using various approaches we are screening for such crucial extracellular ligands in order to study their normal function as well as their role in muscular dystrophy. Mutations in the extracellular matrix component collagen type VI have been found to cause a particular form of congenital muscular dystrophy (type Ullrich). Muscle biopsies and cell lines from patients with congenital muscular dystrophy with and without mutations in collagen type VI will be included in a comparative analysis aimed at understanding the molecular context in which collagen type VI functions and interacts with muscle. By gaining better insight into the molecular events that lead to muscular dystrophy, we are hoping to also open up new avenues for treatment of these devastating disorders.