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The cardiac sarcomere is a complex and highly ordered ensemble of contractile and regulatory proteins designed to generate force.
To maintain functional sarcomeres, precise turnover of proteins is required that balances new protein synthesis and incorporation into the sarcomere with removal and degradation of worn out or damaged proteins. Titin is a giant elastic protein, spanning half a sarcomere, and forms the structural 'backbone' of the sarcomere; yet, the mechanisms regulating the turnover of titin are completely unknown.
The goal of the Lim lab is to use an integrative molecular biology approach to evaluate a number of key aspects in a model they have proposed for titin turnover. As a disease model, the Lim lab has adopted the doxorubicin mouse model which develops a progressive cardiomyopathy characterized by widespread sarcomere disarray. Understanding the molecular mechanisms of titin turnover will provide insight into the regulatory processes of sarcomere turnover and maintenance, and may ultimately lead to novel therapeutic approaches for conditions such as anthracycline cardiomyopathy.