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 I A, due to mutation in the gene encoding Iaminin-alpha2). 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-alpha2-null mice. Our work thus provides proof-of-concept that anti-apoptosis therapy is of potential therapeutic benefit in CMD1 A, 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 CMD1 A.
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 gamma- or delta-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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