Biomechanical characterization of dilated cardiomyopathy causing mutations in human beta-cardiac myosin
Abstract/Contents
- Abstract
- Cardiomyopathies are diseases of the myocardium resulting in heart failure, arrhythmia, and sudden death. Cardiomyopathies represent a major cause of morbidity and mortality in all age groups and recent application of human genomic technologies has revealed thousands of gene mutations that cause inherited and sporadic cardiomyopathies. Many mutations in the beta-cardiac myosin heavy chain (beta-MHC) gene, which encodes the motor that powers ventricular contraction, have been identified to cause inherited cardiomyopathies, including dilated cardiomyopathy (DCM). However, the molecular mechanisms by which these mutations alter the force generation and kinetic properties of the myosin molecule have not been elucidated. As a result, there are no available therapies targeted toward treating the underlying cause of these diseases to date. We have successfully adapted a system to produce recombinant human cardiac myosin motor domain, known as subfragment-1 (S1), using a mammalian myoblast cell line. This technique has allowed us to obtain significant quantities of highly purified recombinant human beta-cardiac myosin S1 for in-depth functional analyses of wild type and DCM-causing mutants. Characterization of biomechanical properties of DCM causing human beta-cardiac S1 demonstrated that DCM mutations results in an overall hypo-contractile state, although the fundamental mechanistic changes that lead to decreased power output vary. In the future, more complex systems can be analyzed by performing assays with regulated thin filaments instead of actin and double-headed myosin motors to gain further insights into the effects of beta-MHC mutations on cardiac myosin function. Furthermore, using emerging induced pluripotent stem cell (iPSC) technology, insights into the effects of these mutations of myosin biomechanical function in vitro can be correlated with their effects on cardiomyocyte function at the cellular level. Further understanding of these mechanisms can guide the search for specific therapeutic targets and lead to the development of small molecules to modulate the effects of the DCM-causing mutations and potentially prevent or reverse this clinically devastating disease.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2014 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Yu, Elizabeth Choe |
|---|---|
| Associated with | Stanford University, Cancer Biology Program. |
| Primary advisor | Spudich, James A |
| Thesis advisor | Spudich, James A |
| Thesis advisor | Assimes, Themistocles, 1970- |
| Thesis advisor | Dunn, Alexander Robert |
| Thesis advisor | Giaccia, Amato J |
| Advisor | Assimes, Themistocles, 1970- |
| Advisor | Dunn, Alexander Robert |
| Advisor | Giaccia, Amato J |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Elizabeth Choe Yu. |
|---|---|
| Note | Submitted to the Program in Cancer Biology. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2014. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2014 by Elizabeth Choe Yu
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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