MAPPING MODIFIERS OF CARDIOMYOPATHY IN MUSCULAR DYSTROPHY

摘要

Abstract Project 2 proposes 1) to identify and study modifiers of muscular dystrophy and 2) to better define the integration between cardiac and pulmonary dysfunction in muscular dystrophy. Ltbp4, the gene encoding latent TGF binding protein, was originally mapped as a modifier of muscular dystrophy using a genomewide strategy. This modifier, identified in mice, was also shown to associate with outcome in human muscular dystrophy. In the last funding period, a second modifier was identified in the form of Anxa6, the gene encoding the protein annexin A6. Annexins bind phospholipid-containing membranes in response to calcium. Using super-resolution confocal microscopy, it was shown that annexin A6 is recruited precisely to the site of sarcolemmal disruption after injury. In other cell types, annexin A1 has been implicated as a key regulator of the innate immune response. Mutations in dystrophin or the sarcoglycan genes lead to sarcolemma instability. The repetitive disruption of the sarcolemma, as occurs in many forms of muscular dystrophy, triggers a cascade of intracellular and extracellular effects. In skeletal muscle, these events are often associated with inflammation, which accelerates the disease course. In cardiac muscle, the contribution of inflammation is less well studied. Recent data suggests that long term treatment with glucocorticoids has benefit that extends to cardiopulmonary function in DMD. Newer data supports the use of mineralocorticoid receptor antagonists to improve cardiac and potentially respiratory function. Therefore, we will investigate the mechanism of action of modifiers, specifically annexin A6 and annexin A1, and their response to steroids and mineralocorticoid receptor blockers. We will also investigate the interactions among modifiers for muscular dystrophy. In the last aim, we will investigate a new modifier locus of the right ventricle in muscular dystrophy. In heart failure, the right ventricle is a key determinant of survival and in muscular dystrophy the right ventricle is additionally compromised by concomitant respiratory insufficiency. Identifying pathways for right ventricular function may help change the course of cardiopulmonary and skeletal muscle dysfunction in muscular dystrophy.