Study of the secondary signaling pathways involved in the pathogenesis of Duchenne Muscular Dystrophy

• Grant number: 12/24098-7
• Support type: Scholarships abroad - Research
• Effective date (Start): March 01, 2013
• Effective date (End): February 28, 2014
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal researcher: Natássia Vieira Serafini
• Grantee: Natássia Vieira Serafini
• Host: Louis M. Kunkel
• Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Research place: Harvard University, Boston, United States

Abstract

Duchenne Muscular Dystrophy (DMD) is an X-linked skeletal myopathy that affects 1:4000 boys and is caused by mutations in the dystrophin gene which results in production of a non-functional protein. Absence of a functional dystrophin causes myofiber degeneration, but the secondary signaling pathways involved in the pathogenesis of DMD remain poorly characterized, and they represent an unexplored territory for therapy. Differently from humans, where nearly all boys carrying null mutations show a severe phenotype, animal models of dystrophin-deficiency show marked differences in the degree of disease severity. The Golden Retriever Muscular Dystrophy (GRMD) dog shows the greatest phenotype variability among all the animal models for DMD, and this variability is likely caused by differences in these secondary signaling pathways. What is protecting these exceptions from the mitigating effect of the dystrophin mutation is a challenging question. Through the study of rare clinical exceptions among the GRMD dogs we aim to identify signaling pathways that can modulate the disease pathogenesis. Our long-term goal is to evaluate if the manipulation of these pathways might be used for therapeutic benefit. To accomplish these goals we will first validate the expression of genes found at skeletal muscle gene expression array of milder affected dogs as compared to severely affected dogs and normal golden retriever dogs. This will be followed by in vivo modulation of the expression of these selected genes using the zebrafish DMD model and the mouse model. (AU)