Grant: Operating Grant

We work on the last steps of muscle development, the establishment of strong muscle attachments and development of the contractile apparatus inside muscles. Mis-regulation of these processes causes a variety of progressive muscle disorders as well as heart failure that we try to understand by dissecting the basic cell biology of a central protein called Zasp52 in the fruit fly model system. Mutations in the closely related human protein Zasp cause muscle disorders, and we and others have shown that Zasp52 and its related mouse protein is necessary for strengthening of muscle attachments to withstand the forces of contraction, and is also required for development of the contractile apparatus inside muscles. Here we propose to analyze the protein partners Zasp52 interacts with to mediate its functions. These protein partners are: 1) talin that upon activation can strengthen muscle attachment. We will analyze how Zasp52 brings talin into its active form. 2) filamentous actin, which is part of the contractile apparatus. We will investigate how Zasp52 organizes actin into larger contractile structures. 3) actinin that can bundle filamentous actin. We will determine how Zasp52 restricts actinin activity to only a few repetitive areas within muscles. We will use biochemical, genetic, and advanced microscopy techniques to investigate the molecular mechanism of Zasp52 function in muscles to learn more about muscle biology and the underlying causes of muscle disorders. As there are many mutations in human Zasp that cause heart and muscle disorders, our work will help understand how these mutations cause disease. This may pave the way for novel therapeutic interventions to better treat muscle disorders in the future.