Dissertation
The role of cardiac troponin T-troponin I interactions in regulating cardiac function in health and disease
Doctor of Philosophy (PhD), Washington State University
01/2012
Handle:
https://hdl.handle.net/2376/4667
Abstract
Alterations of cardiac contractile proteins are a known cause or consequence of heart disease; however, little is known about how particular alterations in cardiac contractile proteins affect contractile function. Highly-coordinated interactions between thin-filament regulatory proteins cardiac troponin C, cardiac troponin T (cTnT), cardiac troponin I (cTnI), and tropomyosin regulate cardiac muscle contraction. Force-generating myosin crossbridges (XBs) further regulate myofilament function by modulating thin-filament protein interactions that lead to contractile activation. cTnT interacts with all other proteins on the thin filament to regulate Ca2+-, sarcomere length (SL)-, and XB-dependent contractile activation. However, there is a lack of knowledge about the functional significance of the cardiac-specific structure of motifs involved in cTnT-cTnI interaction. The significance of this lack of knowledge is highlighted by the fact that structural alterations in and near regions of cTnT-cTnI interactions are associated with heart disease. Therefore, the overall objective of this dissertation is to determine how cTnT-cTnI interactions regulate Ca2+- and SL-dependent activation and underlie contractile function of the heart in cardiac health and disease. The hypothesis of this research was that cardiac-specific structural interactions between helical regions of cTnT and cTnI play a regulatory role in cardiac-specific contractile regulation. We tested our hypothesis by measuring the contractile function and dynamics of cardiac muscle tissue containing variations of cTnT and cTnI within regions where these proteins are known to interact. Specific Aim 1 was designed to probe how cardiac-specific cTnT-cTnI interactions contribute to cardiac-specific contractile function. Specific Aim 2 was designed to determine how disease-related mutations within the cTnT-cTnI interface affect contractile function and examine how myosin XBs further influence the dysfunctional phenotype. In support of our hypotheses, we found that cardiac-specific interactions between cTnT and cTnI were important for cardiac-specific contractile function, and that disease-related mutations the regions of cTnT-cTnI interaction led to functional aberrations consistent with dysfunctional phenotypes seen in cardiac disease. This research is anticipated to significantly contribute to our knowledge of the underlying mechanisms of cardiac pump function and provide insights fundamental to the development of therapies for cardiac dysfunction due to heart disease.
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Details
- Title
- The role of cardiac troponin T-troponin I interactions in regulating cardiac function in health and disease
- Creators
- Steven James Ford
- Contributors
- Murali Chandra (Advisor)Alla Kostyukova (Committee Member)Wenji Dong (Committee Member)Bryan K Slinker (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- Program in Neuroscience
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 264
- Identifiers
- 99900581652801842
- Language
- English
- Resource Type
- Dissertation