|Tipo di tesi||Tesi di dottorato di ricerca|
|Titolo||Notch1 Downregola la Differenziazione nei Cheratinociti Primari Umani|
|Titolo in inglese||Notch1 Downregulates Differentiation in Human Primary Keratinocytes|
|Settore scientifico disciplinare||MED/35 - MALATTIE CUTANEE E VENEREE|
|Corso di studi||Scuola di D.R. in MEDICINA MOLECOLARE E RIGENERATIVA|
|Data inizio appello||2015-04-14|
|Disponibilità||Accessibile via web (tutti i file della tesi sono accessibili)|
La pelle è il più grande e superficiale organo del nostro corpo. La pelle è costituita da epidermide, derma ed ipoderma. Le cellule staminali epidermiche, che risiedono nello strato basale dell’epidermide, possiedono una capacità di auto-rinnovamento nell’arco completo della vita adulta. Queste cellule generano cellule figlie che sono conosciute come cellule Transit Amplifying (TA), che si dividono circa 3-5 volte prima di dare avvio al processo di differenziazione terminale.
Skin is the largest and most superficial organ of our body. It is contituted by epidermis, dermis and hypodermis. Epidermal stem cells, that reside in the basal layer of the epidermis, possess an unlimited self-renewal capacity throughout adult life. These cells generate daughter cells known as Transit Amplifying cells, that divide about 3-5 times before undergo terminal differentiation. Notch proteins are transmembrane receptors involved in cell fate determination. Notch pathway is an hermetic pathway, because it could have diverse roles depending on its doses in different cell contexts. The IAP (Inhibitory of Apoptosis Protein) protein survivin regulates cell cycle and protects keratinocytes from apoptosis. Survivin is overexpressed in cultured keratinocytes stem cells (KSC), and tends to decrease in more differentiated cells. Previous experiments from our laboratory showed that survivin and notch1 proteins decrease during keratinocytes differentiation and ageing. Given that notch1 and survivin pathway are correlated in many cell settings, we investigated the existence of the notch1-survivin axis in normal human keratinocytes by using inhibition and overexpression studies. The administration of DAPT (a -secretase inhibitor, able to block notch signaling) caused a decrease in the levels of activated notch1 as well as a reduction of survivin, which associated with increased keratin10 expression. Coherently, overexpression of activated notch1 in keratinocytes led to an upregulation of survivin, with a slight decrease in the level of keratin10 and involucrin. Interestingly, the addition of calcium to normal keratinocytes induced a decrease of activated notch1, with an increase in involucrin and keratin10. Finally, overexpression of survivin caused a reduction of differentiation markers, while modulating notch1 activation, with an unexpected dual role between stem cells and transit amplifying cells. Taken together, these data indicate that notch1 and survivin could cooperate to negatively regulates differentiation in human keratinocytes.