Our lab in the Heart Institute’s Division of Molecular Cardiovascular Biology has established the means to direct the heart to synthesize normal and mutant proteins in a cardiomyocyte-specific manner. We can turn these on and off at will, allowing us to establish cause-and-effect relationships for normal proteins as well as for those that cause cardiovascular disease.
To understand these relationships, and to establish models in which the pathogenic processes can be studied longitudinally, we have created genetically modified mice and rabbits that synthesize the mutant proteins. Subsequently, we can determine whether or not the protein’s presence causes the effects directly or indirectly.
The goal is to define potential therapeutic targets. Recognizing the utility of these reagents, the scientific community has made good use of them, and over the last decade, we have distributed them freely to more than 1,500 laboratories around the world.
The lab also has interests in exploring how a cardiomyocyte controls its protein turnover. Heart muscle, like all striated muscles, has a remarkable ability to adapt rapidly to external stimuli and changes in workload by adaptation of contractile properties, metabolic flow, cell size and electric behavior. These sweeping changes involve the concerted control of transcription regulation, protein synthesis, protein degradation and metabolic flow. Although the involvement of protein degradation for heart growth seems paradoxical at first, it is now emerging that the replacement of large sets of intracellular organelles and protein assemblies with functionally better-adapted ones requires their controlled destruction. Recent discoveries also suggest that these protein degradation pathways are continually turning over muscle proteins to maintain muscle homeostasis. At the same time, it was discovered that the failure to clear aggregated proteins, or proteotoxicity, is a major factor in hereditary and acquired cardiac and skeletal muscle diseases, as these aggregates are capable of disrupting metabolic capacity, structural integrity, and cellular signaling. The laboratory is studying this system as a potential therapeutic target in pediatric and adult cardiac disease and heart failure.
We are currently conducting research in these areas:
• Structure function relationships for the contractile proteins
• Cardiac disease: Alzheimer’s of the heart?
• Discovery: Application of high-throughput screening techniques for defining new candidates in cardiac disease