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Title: The role of unfolded protein deposits in cardiac dysfunction
Author: Gianni, Davide
ISNI:       0000 0004 2703 5836
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2011
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In this study we investigated the role of unfolded proteins as a toxic insult for cardiomyocytes in idiopathic dilated cardiomyopathy (DCM). We first confirmed the presence of amyloid fibers in DCM cardiomyocytes by histological and ultrastructural analysis, showing their preferentially intracellular distribution. These molecular species seem to coexist with low-complexity β-folded precursors (oligomers) which in our experiments could promote increase of systolic Ca2+ in normal cardiomyocytes and alterations of contractility. Our results suggest that these molecular species trigger the overexpression of UPR components such as GRPs, Chop and Caspase 12. In addition we demonstrated the presence of interactions between presenilins (PS) and Serca2a, suggesting a regulatory role of these Alzheimer’s-related proteins on the Ca2+ pump. The genetic analysis of the presenilin genes in DCM samples identified two undescribed mutations in the promoter of PS1, which appeared to inhibit the expression of the protein. The quantification of the presenilin levels showed a considerable decrease of PS2 associated with an increase of PS1. In order to characterize the protein(s) involved in the aggregasomes, we developed a series of purification protocols, which, unfortunately, did not identify a single protein species. As an alternative approach, we focused on the identification of transcripts differentially expressed in iDCM. Our study introduces an innovative three-group analysis in which we used amyloid samples to eliminate the interference related to the accumulation of unfolded peptides and deriving from the progression of HF. Interestingly we recognized a limited number of iDCM-specific genes, including nestin and DSCR1, which are normally correlated to neural development. In conclusion, our findings open intriguing perspectives to increase our knowledge of the etiology and progression of DCM. However further investigation is required to identify the protein(s) involved in the formation of the aggregasomes and the role of these molecular structures in the etiology of the disease.
Supervisor: Harding, Sian Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral