PROJECT SUMMARY/ABSTRACT Candidate: The proposed career development award is designed to support the transition of Dr. Russell Butterfield to an independent physician-scientist and leader in study of the congenital muscular dystrophies. Dr. Butterfield's PhD work in genetic analysis of complex traits to identify susceptibility loci for autoimmune disease gave him a solid foundation in genetics and computational biology. His clinical training in child neurology and neuromuscular disorders has given him a firm foundation in clinical research. His recent work cataloging genotype-phenotype correlations in collagen VI related muscular dystrophies (COL6-RD) and storing patient samples will provide the necessary patient resource to pursue further studies. He has developed computational skills in the analysis of next-generation sequencing data, including RNA-Seq and exome sequencing. Dr. Butterfield has assembled a strong mentoring team with Dr. Gabrielle Kardon as Primary mentor, and Drs. Robert Weiss and Carsten Bonnemann as co-mentors. With the guidance of his mentors, Dr. Butterfield has designed a career development plan to encompass a 5-year period that will build on his previous experience in genetic analysis and develop new skills in gene-targeting, mouse model development, and cellular and molecular biology techniques, and proteomics. During the award period he will receive formal training in gene targeting, microscopy, mass spectroscopy and proteomics, mouse phenotyping, research administration, and leadership. His mentors provide expertise and experience that is both distinct and complementary. They are internationally recognized experts with long and successful track records of funding and trainee mentorship. The work proposed here will fill the gaps in his training in cellular and molecular biology and genetic manipulation of model organisms. In addition, this research will allow him to position himself as a leader in the congenital muscular dystrophies and as a successful independent investigator Research: COL6-RD are inherited disorders of collagen VI characterized by progressive muscle weakness and a combination of distal joint laxity and proximal joint contractures. COL6-RD are increasingly recognized disorders accounting for up to 30% of patients with congenital muscular dystrophy (CMD). Children with COL6-RD have life-long neurologic, orthopedic, and pulmonary complications necessitating complex, multispecialty care. There are no treatments. Phenotypic heterogeneity is the hallmark of COL6-RD with a spectrum of severity in patients from the very severe Ullrich congenital muscular dystrophy (UCMD) to the milder Bethlem myopathy (BM). Factors controlling severity in COL6-RD patients are largely unknown. Dr. Butterfield's research plan incorporates 3 related aims with a goal to identify factors that control phenotypic heterogeneity in COL6-RD and develop a mouse model that reflects the heterogeneity seen in human COL6- RD. In the first ai...