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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/10990/733

Autori: Caragnano, Angela
Supervisore afferente all'Università: DI LORETO, CARLA
Centro di ricerca: DIPARTIMENTO SCIENZE MEDICHE E BIOLOGICHE - DSMB
Titolo: Autophagy and inflammation in the pathogenesis of idiopathic dilated cardiomyopathy
Abstract (in inglese): Background: Idiopathic dilated cardiomyopathy (iDCM) is a disease of cardiac muscle characterized by dilatation, in particular of left ventricle, and systolic dysfunction in absence of other pathological conditions note and it it is burdened by a serious morbidity and mortality. Recent literature data indicate that the loss of proteostasis is an important pathophysiological mechanism. Aims: Starting from the observation that proteins aggregate as amyloid accumulations in cardiomyocytes of patients affected by iDCM, it was evaluated the hypothesis of a defect in the ubiquitin-proteasome system (UPS). It has been shown that aggresome stimulates an increase of autophagic flow so we wanted to assess the presence of elements indicative autophagy-lysosomal pathway (ALP) alterations. For this reason, we analyzed the presence of punctae of LC3 and levels of p62. An effect of the arrest of the autophagic/lysosomal pathway follows the accumulation of dysfunctional mitochondria within the cell. We evaluated also the accumulation of mitochondria positive to Parkin1, suggesting a defect in the removal of dysfunctional mitochondria. Methods and Results: we compared 48 hearts of patients affected by iDCM, collected at the time of transplant, with 18 control hearts. We studied autophagic flux alteration, mitochondrial dysfunction, activation of the damage response to double-stranded DNA, inflammasome activation, NF-kB activation and myocyte hypertrophy. Furthermor we compared cardiac stem cells obtained by explanted hearts of iDCM patients and donors studying senescence, proliferation and lysosomal membrane permeabilization. Conclusions: data obtained suggest that patients affected by iDCM present a vicious cycle characterized by loss of proteostasis, defects of autophagic flux, accumulation of dysfunctional mitochondria, increase of free intracellular radical, activation of the cellular DNA damage response, activation of inflammatory response with further stimulus to myocyte hypertrophy and worsening proteostasis.
Parole chiave: Idiopathic dilated cardiomyopathy; Autophagy; Inflammasome; Proteostasis senescence; Lysosomal membrane permeabilization
MIUR : Settore MED/08 - Anatomia Patologica
Lingua: eng
Data: 17-mag-2016
Corso di dottorato: Dottorato di ricerca in Scienze e tecnologie cliniche
Ciclo di dottorato: 27
Università di conseguimento titolo: Università degli Studi di Udine
Luogo di discussione: Udine
Altre informazioni: Co-supervisore: Antonio Paolo Beltrami - Struttura di aggregazione: Istituto di anatomia patologica (c.s.l.), Azienda ospedaliero universitaria "s. Maria della misericordia"- Udine
Citazione: Caragnano, A. Autophagy and inflammation in the pathogenesis of idiopathic dilated cardiomyopathy. (Doctoral Thesis, Università degli Studi di Udine, 2016).
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