The role of Notch signaling and epidermal cytokines in the Hailey-Hailey disease pathogenesis and in the DNA damage response [Tesi di dottorato]

Hailey-Hailey disease (HHD) is a skin disorder linked to mutations in the ATP2C1 gene encoding a Ca2+/Mn2+ ATPase. ATP2C1 loss of function in keratinocytes leads to the loss of cell-to-cell adhesion in the suprabasal skin layers. The disorder is manifested as blistering skin lesions that do not heal and susceptible to microbial infections. Additionally, patients with squamous/basal cell carcinomas arising in the skin lesions have been described. There is no long-term treatment known to be effective in reducing the manifestations of HHD. The identification of compounds with fewer side effects compared to those used in the SOC treatment is highly desirable and could be reached by understanding the molecular mechanisms underlying the disorder. We previously found that HHD keratinocytes have increased oxidative stress that is associated with impaired proliferation, differentiation and DNA damage repair; these aspects are linked to the decreased action of some detoxifying systems and/or to deregulation in molecular pathways crucial for skin homeostasis such as the Notch1 signaling. Notch1 signaling influences many physiological aspects of the skin including differentiation, wound repair and also the DNA damage response. Moreover, HHD keratinocytes are characterized by deregulation in cytokines expression. The aims of my PhD thesis were designed to dissect the relationship between DNA damage engagement, inflammatory signaling, oxidative stress and Notch1 deregulation in HHD development.

diritti: info:eu-repo/semantics/openAccess
In relazione con info:eu-repo/semantics/altIdentifier/hdl/11573/1549583
TALORA, Claudio
Valutatori esterni: F. Bernassola, C. Missero
Settore MED/04 - - Patologia Generale

Tesi di dottorato. | Lingua: Inglese. | Paese: | BID: TD21003185