PROJECT SUMMARY Heart failure secondary to cardiac involvement of muscular dystrophy is a main driver of morbidity and mortality in patients with certain subtypes of muscular dystrophy, including Duchenne and Becker muscular dystrophy. The dystrophin complex connects the skeletal and cardiac muscle cytoskeleton to the extracelluar matrix. Mutations in genes that encode the proteins of the dystrophin complex cause muscular dystrophy and cardiomyopathy. Induced pluripotent stem cells (iPSCs) can be created from patient cells and differentiated into cardiomyocytes (iPSC-CMs) to provide patient/genotype specific models of disease. These models are somewhat limited by their immaturity, including in their expression of the dystrophin complex. Correct display of the dystrophin complex in iPSC-CMs is essentially if this promising tool is to useful in testing new therapeutic strategies for cardiomyopathy secondary to muscular dystrophy. This proposal presents preliminary data that demonstrates that micropatterned surfaces combined with maturation media can improve the expression and localization of the dystrophin complex in iPSC-CMs. It aims to fully characterize the dystrophin complex of iPSC-CMs and identify conditions that improve maturation of the complex using micropatterned patterned surfaces. Using this model, several therapeutic strategies for muscular dystrophy will be assessed using patient-derived iPSC lines from patients with 3 different subtypes of muscular of muscular dystrophy that affect the dystrophin complex. This NRSA individual postdoctoral fellowship is to facilitate Dr. Fullenkamp's development as a physician-scientist. Dr. Fullenkamp will carry out this work at the Center for Genetic Medicine at Northwestern University under the sponsorship of Dr. Elizabeth McNally. Dr. Fullenkamp is a participant in the Physician Scientist Training Program (PSTP) and a Cardiovascular Disease Fellow at Northwestern University. He has completed the majority of his clinical training and this fellowship will support the research phase of his training. As a physician-scientist, Dr. Fullenkamp will benefit uniquely from the mentorship of Dr. McNally who is an internationally recognized physician-scientist with specialization in cardiac genetics and muscular dystrophy. The strong engineering resources of Northwestern University will allow Dr. Fullenkamp to bring engineering tools to this project, while at the same time learning new skills in molecular and cellular biology and genetics.