Project 171081

Patients with Duchenne Muscular Dystrophy (DMD) suffers from severe muscle weakness and injury and die of respiratory failure because of inability of the respiratory muscles to ventilate the lungs. The defect in these patients is loss of dystrophin, a protein localized at the cell membrane of skeletal muscle fibers. Recent studies suggest that improving neovascularization inside skeletal muscle improves the recovery of muscles from injury and enhanced muscle fiber performance. Angiopoietin-1 is a newly discovered angiogenesis factor that improves neovascularization in many models of ischemia. In addition, this protein exerts positive effect on cellular survival and proliferation. In this application, we propose a comprehensive program to evaluate the use of angiopoietin-1 to improve the ability of the respiratory muscles to recover from injury in a model of muscular dystrophy. We will study first the efficiency of increasing angiopoietin-1 expression on the ability of the respiratory muscles to regenerate and recover from injury elicited by a chemical agent (snake venom) applied directly to these muscles and in naturally occurring injury in a mouse model of muscular dystrophy (mdx mice). An increase in angiopietin-1 will be achieved by crossbreeding genetically engineered mice with mice with muscular dystrophy or by using special viruses which are capable of over-expressing angiopoietin-1 protein selectively in skeletal muscles. The second objective of the proposal is to study the effects of angiopoietin-1 on the ability of skeletal muscle stem cells to respiratory muscle injury. We will isolate these cells from normal mice and mdx mice and evaluate the direct effects of angiopoietin-1 on the growth rate and the ability of these cells to migrate to the site of injury. The final objective of the proposal will focus on molecular mechanisms through which angiopoietin-1 improves the capacity of skeletal muscle stem cells to repair muscle injury.

using angiopoietin-1 gene therapy to improve respiratory muscle regeneration in a mouse model of muscular dystrophy