Idiopathic immune myopathies are a group of disorders causing chronic damage to skeletal muscle due to extensive inflammation triggered by an autoimmune response. This chronic inflammation state leads to degeneration of muscle structure and function resulting in severe proximal muscle weakness. T cell- and antibody-mediated processes are known to be involved in the progression of disease, however, the mechanism leading to pathogenesis remains unknown. Current treatment options for myositis are minimal and focus on the use of broad-spectrum immunosuppressive drugs and corticosteroids. While these treatments exhibit a degree of efficacy for the acute management of myositis, systemic suppression of the immune system often leads to significant complications. This project will examine the contribution of sarcolemmal membrane repair to the pathogenesis of myositis. The membrane repair response is initiated by the influx of extracellular calcium at the site of injury. This influx triggers trafficking of intracellular vesicles to the sarcolemmal membrane, thereby forming a patch that restores membrane barrier function and allows the injured cell to survive. Our work has helped to identify TRIM72 (also known as MG53), a member of the Tripartite Motif (TRIM) family of intracellular proteins, as a critical component of the membrane repair process. Our preliminary studies identified novel autoantibodies against TRIM proteins yet to be associated with myositis and identified increases in TRIM protein expression levels in human myositis skeletal muscle biopsies. We also find that antibodies against TRIM72 can compromise membrane repair. Our driving hypothesis is defects in membrane repair associated with the progression of myositis lead to TRIM protein exposure to the extracellular space and that the autoantibodies produced against TRIM proteins further compromise membrane repair and exacerbate inflammation. We propose to test this hypothesis using three specific aims.
Aim 1 defines the mechanistic role of TRIM72 antigen presentation on membrane fragility associated with myositis.
Aim 2 determines if autoantibodies against skeletal muscle proteins linked to the membrane repair process are sufficient to compromise membrane repair.
Aim 3 evaluates the efficacy of increasing membrane repair capacity as a novel therapeutic strategy to treat myositis. These studies should allow us move towards our long term goal is to improve clinical outcomes for patients suffering from idiopathic immune myopathies such as myositis by elucidating the mechanisms leading to chronic inflammation and muscle degeneration. This would allow for the development of novel therapeutic approaches for myositis.
In this proposal we will test a novel mechanism leading to the onset and progression of myositis and evaluate the efficacy of a potential therapeutic intervention. Our long term goal is to improve clinical outcomes for patients suffering from idiopathic immune myopathies by elucidating the mechanisms leading to chronic inflammation and muscle degeneration.
