Molly E. McCue, Ph.D. - US grants

DESCRIPTION (provided by applicant): Polysaccharide Storage Myopathy (PSSM) is a novel inherited glycogenosis characterized by myoplasmic accumulation of abnormal polysaccharide and clinical myopathy. We have identified a gain of function mutation in the GYS1 gene encoding the skeletal muscle is form of glycogen synthase in horses with PSSM, which results in an amino acid substitution in a highly conserved region of the enzyme. We have also identified a second, unique non-GYS1 form of PSSM in about 20% of cases. Horses are an ideal model for the study of heritable muscle disease due to extended accurate pedigrees from founder stallions, their natural athleticism which makes metabolic disease readily apparent, and the ease of performing muscle diagnostic testing. The overall goal of this project is to use both forms of PSSM to define new mechanisms regulating skeletal muscle glycogen synthase activity and glycogen metabolism in health and disease. Specific Aim 1 of this project will identify the functional basis for the GYS1 mutation through protein expression in E. coli and GS activity measurements, and Specific Aim 2 will determine the genetic basis of the non-GYS1 form of PSSM through whole genome association mapping with SNP markers. Candidate and environment: Dr. Molly McCue has DVM, MS and PhD degrees, and is board certified in Large Animal Internal Medicine. She has secured a tenure track faculty position with a research program focusing on the clinical, epidemiologic, genetic and functional basis of large animal models of neuromuscular disease. Her short term goals are to build the skills needed to define the genetic and functional basis of disease. The training program is designed to allow Dr. McCue to develop these skills while also developing other tools needed to succeed in academic medicine. The University of Minnesota has a strong program in comparative medicine and a highly collaborative environment which will be integral to Dr. McCue's success.

Project Summary/Abstract The Comparative Medicine and Pathology training program was initiated in the fall of 2003 and provides state- of-the-art research training to veterinarians. Five years of continuing support are requested in the present application, including support for six trainees in each year of the program. It is anticipated that the majority of these individuals will have completed a residency in medicine, surgery, or pathology prior to entering the training program. Selection criteria will include: 1) strong interest in research and a desire for a career in academic veterinary medicine; 2) academic credentials and performance during clinical training/residency; and 3) desirable personal characteristics, including integrity, perseverance, and oral and written communications skills. The training program is located in the College of Veterinary Medicine at the University of Minnesota and is directed by Drs. Cathy Carlson, David Brown, and Molly McCue. Thirty-three faculty mentors, all members of the Comparative and Molecular Biosciences (CMB) and/or Veterinary Medicine (Vet Med) graduate programs, will participate in the training program. These individuals represent a diverse group of disciplines, including pharmacology, cell biology, infectious disease, neurobiology, physiology, genetics, molecular biology, and orthopedics. Trainees without a PhD degree will pursue a PhD in the CMB or Vet Med graduate program, well- organized, multidisciplinary graduate programs created to focus graduate education efforts by faculty interested in comparative biomedical sciences and the molecular mechanisms responsible for human and animal health and disease. The goals of our programs are to provide students with the broad-based knowledge, quality communication skills, and advanced research training essential for a career as independent investigators.