Our recent studies have identified a therapeutic approach, based on inhibition of apoptosis, that significantly ameliorates disease in mice that are models for the most common type of human congenital muscular dystrophy (CMD Type IA, due to mutation in the gene encoding Iaminin-a2). Specifically,we found that either inactivation of Bax (a pro-apoptosis protein) or muscle-specific overexpression of Bcl-2 (an anti-apoptosis protein) produced a several-fold increase in lifespan and increased the growth rates and muscle functions of Iaminin-a2-null mice. Our work thus provides proof-of-conceptthat anti-apoptosis therapy is of potential therapeutic benefit in CMD1A, but key questions must be answered before the potential of anti-apoptosis therapy is fully understood. We propose three sets of experiments to advance our understanding of anti- apoptosis approaches to therapy in neuromuscular diseases.
For Specific Aim 1, we will use the Lama2-nu mouse model to test known anti-apoptosis drugs, such as minocycline and caspase inhibitors, as potential pharmacological therapies for CMD1A.
For Aim 2, we will combine different types of interventions, e.g. Bax inactivation and IGF-1 treatment, to examine mechanisms of pathogenesis and identify improved therapies.
For Aim 3, we will determine if additional myopathies with respiratory muscle involvement, specifically those caused by loss of 8-or y-sarcoglycan, can be ameliorated by targeted alterations of Bcl-2 family members. Our goals are to extend our understanding of mechanisms of pathogenesis in muscle diseases and to lay the groundwork necessary for translation of anti-apoptosis therapies into clinical practice. Lay summary: Our work will evaluate a therapeutic strategy for specific neuromuscular diseases. These diseases are highly debilitating and currently have poor treatment options.
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