Emery-Dreifuss muscular dystrophy (EDMD) is a genetically heterogenous syndrome that results from mutations in genes encoding nuclear envelope proteins. It is characterized by scapulohumeral-peroneal myopathy, early joint contractures and a lethal dilated cardiomyopathy with conduction defects. Mutations in EMD, which encodes an integral protein of the inner nuclear membrane called emerin, cause X-linked EDMD. Mutations in LMNA, which encodes A-type lamins, cause autosomal EDMD. Lamins are intermediate filament proteins lining the inner nuclear membrane. Extremely rare cases of EDMD-like disorders have been linked to mutations in genes encoding other nuclear envelope proteins, including TOR1AIP1 that encodes lamina- associated polypeptide 1 (LAP1), an integral protein of the inner nuclear membrane. Emerin, A-type lamins and LAP1 all interact with each other and indirectly with muscle cytoskeletal structural proteins. Our research during previous cycles of this continuing project has provided new insights into the pathobiology of EDMD. However, there are still challenges to deciphering the pathogenic mechanisms underlying the heart and skeletal muscle pathology in EDMD and in translating fundamental discoveries towards the treatment of patients. One is the lack of small animal or adequate cellular models of X-linked EDMD caused by emerin deficiency. Another is developing approaches to determine if skeletal muscle pathology occurs primarily as a result of defects in differentiated myofiber structural integrity, in regeneration of damaged fibers or both. This proposal addresses these challenges. Our first hypothesis is that similar pathogenic cell signaling and gene expression abnormalities are responsible for dilated cardiomyopathy in both X-linked and autosomal EDMD. Our second hypothesis is that alterations in EDMD-associated proteins affect both the structural integrity of differentiated skeletal muscle fibers and the ability of injured muscle to regenerate.
Specific Aim 1 will address the first of these hypotheses. We will generate a mouse model of cardiomyopathy in X-linked EDMD as well as isogenic cultured cardiomyocytes with EMD, LMNA and TOR1AIP1 mutations. This will allow us to determine if the same cell signaling and gene alterations occur in the heart in X-linked and autosomal EDMD.
Specific Aim 2 will investigate the effects of EDMD-causing gene mutations on differentiated skeletal muscle. To do so, we will generate mice in which the encoded proteins can be depleted from differentiated adult myofibers and examine the pathological, physiological and gene expression abnormalities that occur.
Specific Aim 3 will examine the role of EDMD-associated proteins in skeletal muscle regeneration. This will be accomplished by depleting the proteins specifically from skeletal muscle satellite cells and assessing regeneration after injury. Successful completion of these Aims will advance our understanding of the cardiac and skeletal muscle pathobiology in X-linked and autosomal EDMD and provide novel model systems to test therapies.
Thousands of people in the United States suffer from Emery-Dreifuss and genetically-related forms of muscular dystrophy, inherited disorders for which there are no cures. This project will use novel mouse and cellular models to understand how mutations in different genes can cause Emery-Dreifuss muscular dystrophy and uncover cellular abnormalities that may be targeted by new therapies.
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