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Crispino, Giulia (2011) MOuse models of hereditary hearing loss: connexin expression and functional analyses. [Tesi di dottorato]

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Abstract (inglese)

Single point mutations in Connexins 26 or 30 (Cx26, Cx30), codified respectively by GJB2 and GJB6 gene of the DFNB1 locus, provoke genetic non syndromic hearing deafness in pre lingual stage. In the inner ear, expression of Cx26 and Cx30 is mainly concentrated in non sensory cells in the Organ of Corti (OoC), known as supporting cells, and in the spiral ligament, where they form connexin channels. The rescue of the expression of wild type connexin is one of the possible therapies for patients, and this can restore cellular network communication of defective connexin gap junctions and hemichannels (Ortolano, 2008 1207).
In this work we characterized by immunofluorescence the expression of connexin 26 and 30 in the double mutant Cx26Sox10Cre mice during inner ear development, from P5 to adult age, specially in the OoC. We addressed kind of cellular degeneration, more evident in the basal turn of the cochlea, by the absence of the connexin channels. In adult mice, partial obliteration of Cxs leaded to a profound hearing loss, probed by ABR registrations, and a reduction of endocochlear potential. Cochlear organotypic cultures from mutant mice probed by gap-FRAP experiments presented an unpaired cell-cell communication.
We have also described an in vivo gene therapy approach that can be used to restore the expression of Cxs in mice using a Bovine Adeno Associated virus, BAAV. The BAAV is a very safe tool because it is not toxic, not pathogenic, and replicative defective in host cells. The transduction of genes occurs mainly on supporting cells, where the connexins are expressed (Ortolano, 2008 1207).
Our studies identified which age is resonable to start a gene therapy in order to get the best results on hearing. For this therapeutic study, technique such as canalostomy, which previously were described in adult mice, were standardized in P4 mice. We reported for the first time that this kind of surgery in such young mice is not affecting hearing function, and that, so far, we can manipulate gene expression in vivo, by deleting Cx26 gene in few cells in Cx26loxP/loxP mice by a Cre recombinase, codified by the BAAV genome.

Abstract (italiano)

Mutazioni puntiformi nelle Connessine 26 o 30 (Cx26, Cx30), codificate rispettivamente dai geni GJB2 e GJB6 nel locus DFNB1, provocano sordità ereditaria non sindromica in età perlinguale. Nell’orecchio interno, l’espressione della Cx26 e Cx30 è concentrata soprattutto nelle cellule non sensoriali, o cellule di supporto, dell’ Organo di Corti (OdC), e nel legamento spirale, dove formano canali di connessine. Il ripristino dell’espressione delle connessine sane è una possibile terapia per pazienti non udenti, che permetterebbe il recupero delle comunicazioni della rete cellulare attraverso giunzioni gap ed emicanali di connessine funzionali (Ortolano, 2008 1207).
In questo lavoro, abbiamo caratterizzato, attraverso tecniche di immunofluorescenza, l’espressione delle Cx26 e Cx30 in topi transgenici Cx26Sox10Cre, durante lo sviluppo dell’orecchio interno, da P5 all’età adulta, in particolare nell’OdC.
Abbiamo notato una degenerazione cellulare maggiormente evidente nel giro basale della coclea, dovuto all’assenza di canali di connessine. Nei topi adulti, si è notata una marcata perdita uditiva dovuta alla parziale mancanza di connessine, a seguito di registrazioni di ABR, e una riduzione del potenziale endococleare.
Esperimenti di gap-FRAP condotti in colture organo tipiche di coclea dai topi mutanti hanno rivelato una notevole riduzione delle comunicazioni cellulari.
Abbiamo inoltre descritto un approccio in vivo per una terapia genica, che potrebbe essere usato per ripristinare l’espressione delle connessine, utilizzando un virus adeno-associato bovino (BAAV). Tale virus rappresenta uno strumento molto sicuro, poiché non è tossico, non è patogeno e non si replica nelle cellule ospiti. La trasduzione attraverso questo vettore interessa soprattutto le cellule di supporto, dove sono maggiormente espresse le connessine (Ortolano, 2008 1207).
I nostri studi hanno identificato la migliore età da cui iniziare una terapia genica, al fine di ottenere i risultati migliori. Per questi studi terapeutici, abbiamo perfezionato una tecnica ampiamente utilizzata in topi adulti, applicandola in topi di 4 giorni. Abbiamo verificato, per la prima volta, che questa metodica anche applicata a topi così giovani non interferisce con la funzionalità uditiva. Inoltre, ad ora, abbiamo potuto manipolare l’espressione genica in vivo, eliminando il gene della Cx26 in alcune cellule di topi Cx26loxP/loxP attraverso l’espressione di una Cre ricombinasi codificata dal genoma del BAAV.

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Tipo di EPrint:Tesi di dottorato
Relatore:Mammano, Fabio
Dottorato (corsi e scuole):Ciclo 23 > Scuole per il 23simo ciclo > BIOSCIENZE > NEUROBIOLOGIA
Data di deposito della tesi:NON SPECIFICATO
Anno di Pubblicazione:29 Gennaio 2011
Parole chiave (italiano / inglese):cochlea, deafness, connexin
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/17 Istologia
Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Area 05 - Scienze biologiche > BIO/18 Genetica
Struttura di riferimento:Centri > Centro Interdipartimentale di ricerca per lo Studio dei segnali cellulari
Codice ID:3797
Depositato il:19 Lug 2011 10:29
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