Monocytes and Dysferlinopathy: Role of Thrombospondin-1
A common characteristic of dysferlinopathy is an exuberant inflammatory response with abundant macrophage infiltration that may contribute to the pathogenesis of the disease. Our specific hypothesis for this proposal is that thrombospondin-1 (TSP-1) promotes a destructive monocyte/macrophage response that exacerbates muscle damage. Our initial studies indicate that TSP-1 levels correlate with macrophage accumulation and phagocytosis leading to loss of muscle mass in dysferlin deficient mice. We will determine whether TSP-1 plays a causal role in disease progression in dysferlin deficient mice by cross-breeding BlaJ mice with TSP-1 knockout mice and determining whether loss of TSP-1 activity ameliorates the disease phenotype in BlaJ mice. This project will provide insight into whether targeting the inflammatory response, and mononcytes/macrophages in particular, is a viable approach for ameliorating disease progression in dysferlinopathy.