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Title: The role of CaMKIIδ in modulation of NF-ҡB signalling in normal and hypertrophied mouse hearts
Author: Martin, Tamara Patricia
ISNI:       0000 0004 2739 8936
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2012
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Calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) has been identified as a central regulatory molecule in the heart, important not only in modulating normal cardiac function, but also in promoting cardiac hypertrophy and heart failure. The focus for CaMKIIδ action in the myocardium has been placed upon the cardiac myocytes due to the fundamental role these cells play in cardiac contractility. However, the non-contractile cells of the heart, predominantly cardiac fibroblasts (CFs), are now emerging as equally important candidates for modulating cardiac function. CaMKIIδ is well established as a key modulator of excitationcontraction coupling in normal and diseased myocardium, however additional roles for this enzyme in other areas of cardiac function and dysfunction are less well understood. Cardiac inflammation and fibrosis are two key features of various cardiomyopathies. The role of CaMKIIδ in either or both has yet to be established. CFs, through their proliferative capacity and potential to secrete various growth factors and pro-inflammatory cytokines are pivotal in regulating both fibrosis and inflammation within the myocardium. However, the regulatory mechanisms underlying these features remain poorly understood. This study has focused on (i) identifying a link between CaMKII and Nuclear Factor kappa B (NF-κB) pro-inflammatory signalling in the heart, (ii) development and characterisation of a novel minimally invasive (MTAB) model of cardiac hypertrophy in mice, and (iii) assessing alterations in both CaMKII and NF-κB signalling following hypertrophy. Importantly there has been a focus on CFs in this work, providing new information about the role of CaMKII in these cells in both normal and hypertrophied hearts, including for the first time evidence for CaMKII modulation of pro-inflammatory NF-κB signalling in normal adult murine CFs. A direct interaction between CaMKIIδ and NF-κB signalling has been demonstrated at the level of inhibitory- κB kinase β (IKKβ) using Surface Plasmon Resonance (SPR). Successful development of the MTAB model has allowed assessment of hypertrophic development and progression. One week following surgery, there is evidence for both systolic and diastolic dysfunction. Characteristic features of significant cardiac hypertrophy are evident four weeks following surgery. These include an increase in heart size, cardiac contractile dysfunction and increased cardiac fibrosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available