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Our research team includes outstanding faculty, expert staff and trainees committed to understanding the mechanisms underlying genetic diseases that affect heart and muscle. Many different genes and genetic variants can lead to heart dysfunction and irregular rhythms, and some of these same genes also cause muscle wasting and weakness. It is our goal to better understand how, when, and why these diseases develop and progress. In some cases, individuals with genetic mutations may be protected from developing disease, and we are interested in using genetics to define the pathways that protect these individuals. 

Our team uses broad genome profiling to identify pathogenic variants and genetic modifiers.  We then study how these gene changes cause heart and muscle dysfunction using tools like individualized pluripotent stem cells, which can be engineered into heart tissues. We also use mice and other genetic models to mirror the human condition.  With expansion of gene editing, we are testing how to correct genes and mutations to treat genetic disorders. Our research team is a supportive teaching and training environment for graduate students and postdoctoral fellows. We also host undergraduate and postbaccalaurate trainees who are interested in learning analytical and experimental approaches to human genetic disorders. 

Research Focus

Defining and understanding rare genetic variation

In the clinical setting, genetic testing for inherited cardiomyopathy and skeletal muscle disease relies on gene panels, where hundreds of genes are assessed simultaneously. With the improvements in sequencing technology like massively parallel next generation sequencing and long read sequencing, it is now more feasible to use broad-based sequencing to identify novel genes and alleles responsible for human disease. To facilitate the analysis of genome sequencing, we harness the power of high-performance computing to improve the speed and accuracy of genome analysis.

Identifying modifiers of genetic disease

The rationale to search for genetic modifiers is stimulated by the observation that the same individual mutation often results in a range of phenotype from mild to severe. Discovering genetic modifiers is useful because it uncovers pathways useful for therapeutic targeting and also because these modifiers can better predict prognosis. We conducted unbiased genomewide mapping for modifiers using mice with muscle and heart disease. Using an intercross strategy, we conducted genomewide scans and have now identified multiple genetic modifiers, including Ltbp4 and Anxa6. Ltbp4 encodes the latent TGF-beta binding protein 4 and has now been shown to modify human disease, and we are developing novel therapies based on this protein and its mechanisms of mediating fibrosis.

Membrane repair proteins

Mutations in dysferlin, a distinct membrane-associated protein in muscle, also lead to inherited muscle disease. Loss of dysferlin is associated with delayed muscle membrane repair and resealing after disruption of the plasma membrane. We characterized myoferlin, a protein highly related to dysferlin. Both myoferlin and dysferlin are multi C2 domain-containing proteins. We were the first to demonstrate that C2 domains of dysferlin and myoferlin bind phospholipids in a Ca2+ sensitive manner. The annexin proteins, including annexin A6, are essential proteins for the membrane repair process.   

Mutations in nuclear membrane proteins, especially the genes encoding lamin A/C, emerin, and nesprin, also lead to genetically mediated heart and muscle. These mutations also affect the heart where they target the cardiac conduction system. The mechanism by which mutations in the genes encoding these broadly expressed proteins lead to tissue specific phenotypes is not fully understood and we are investigating the function of these proteins.

Many mutations that cause heart failure disrupt cardiac metabolism. We are testing mouse models and human cells to learn the relationship between cardiac metabolism and progression to heart failure.

Recent Findings

  • Defining common and rare variation for heart failure, cardiomyopathy, and arrhythmias
  • Discovering new modifiers for cardiomyopathy
  • Developing novel proteins to treat muscular dystrophy
  • Investigating new approaches and pathways for glucocorticoid treatment for muscle disease

Current Projects

  • Using genomic tools to evaluate noncoding variation in cardiomyopathy
  • Studying the role of the extracellular matrix in muscular dystrophy
  • Defining mechanisms of cardiomyopathy using engineered heart tissues generated from induced pluripotent stem cells
  • Testing gene editing strategies to improve heart function