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Gambalunga, Alberto (2008) Identificazione e caratterizzazione di nuovi inibitori del poro della transizione della permeabilità  mitocondriale. [Tesi di dottorato]

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Abstract (inglese)

We have characterized the mitochondrial and cellular effects of two molecules identified by Genextra's S.p.A from a chemical library by high throughput screening (HTS) designed to identify novel inhibitors of the mitochondrial permeability transition pore (PTP). The screening, based on in vitro calcium-induced mitochondrial swelling, yielded several PTP inhibitory compounds and two of them, CngPtP003 and CngPtP006, have been selected for the present study. We studied the inhibitory properties of CngPtP003 and CngPtP006 on PTP in isolated mouse liver mitochondria with the Calcium Retention Capacity (CRC) assay, and the inhibitory profiles compared with those displayed by the well known PTP inhibitor cyclosporin A (CsA). From this first set of experiments we confirmed that both compounds are PTP inhibitors with different biological potency and efficacy, and that their molecular targets are not the same as that of CsA, with which both compounds displayed additive effects. In a second set of experiments we studied the mitochondrial effects of CngPtP003 and CngPtP006 in intact HeLa cells with the tetramethylrhodamine methyl ester (TMRM) assay, which measures the mitochondrial membrane potential. We found that only CngPtP003 is able to protect the cells from the depolarization and from cell death caused by the PTP inducer arachidonic acid. Lack of inhibition by CngPtP006 data has been confirmed both in HeLa isolated mitochondria and in several human permeabilized cell lines, indicating that the inhibitory properties of CngPtP006 are limited to mouse mitochondria, which were used in the primary screening. These results validate the HTS approach for the identification of novel PTP inhibitors, whose suitability for drug development is currently under investigation.

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Tipo di EPrint:Tesi di dottorato
Relatore:Bernardi, Paolo
Dottorato (corsi e scuole):Ciclo 20 > Scuole per il 20simo ciclo > BIOSCIENZE > BIOLOGIA CELLULARE
Data di deposito della tesi:31 Gennaio 2008
Anno di Pubblicazione:31 Gennaio 2008
Parole chiave (italiano / inglese):PTP, mitocondri, inibitori
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/09 Fisiologia
Struttura di riferimento:Centri > Centro Interdipartimentale di servizi A. Vallisneri
Dipartimenti > Dipartimento di Scienze Biomediche Sperimentali
Codice ID:284
Depositato il:02 Ott 2008
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