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Please use this identifier to cite or link to this item: http://hdl.handle.net/10805/2561

Title: STUDY OF THE MOLECULAR ALTERATIONS AND TREATMENT OF HAILEY-HAILEY DISEASE
Authors: MANCA, SONIA
Tutor: TALORA, CLAUDIO
Keywords: HAILEY-HAILEY DISEASE
MOLECULAR ALTERATIONS
NRF2
OXIDATIVE STRESS
Issue Date: 14-Feb-2014
Abstract: Hailey-Hailey Disease (HHD) is a chronic, recurrent blistering rare disorder, clinically characterized by erosions occurring primarily in intertriginous regions and histologically by suprabasal cutaneous cells separation (acantholysis). Despite a strong relationship between mutations in ATP2C1 gene, encoding for hSPCA1 calcium pump, manifestations of the disease occurs with high variability between patients. In our previous studies we used primary keratinocytes derived from lesions or normal skin of patients with HHD, reporting several molecular changes related to manifestation of the disease. We reported that oxidative stress has a specific role in the pathogenesis of HHD by regulating the expression of important factors, which play a crucial role in keratinocyte homeostasis. In this study, we analyzed the miRNA expression profile of keratinocytes derived from lesional skin of HHD-patients, and we found that miR-125b, in particular, is upregulated. Furthermore, we identified both, Notch1 and p63, as direct targets of mir-125b. In silico analysis of regulatory motifs in miR-125b promoter revealed TF-binding sites of genes known to function in the oxidative-stress response, such as ARNT, MARE or NF-KB. Additionally, we found that miR-125b expression is increased by an oxidative stress-dependent mechanism. Moreover, we saw that Nrf2, a transcription factor that plays a key role in cell response to oxidative stress, is downregulated in keratinocytes derived from lesional skin. Furthermore, our results show that Nrf2 is an important target of α-MSH-analogue, NIe4-D-phe7-α-MSH (afamelanotide) and treatment of keratinocytes with NIe4-D-phe7-α-MSH restored the proliferative capability of lesions-derived keratinocytes. Therefore, to assess the clinical potential of this compound, we conducted a phase II open-label pilot study on two patients with several long-standing skin lesions. Both patients treated had experienced 100% clearance of HHD lesions 60 days after the first injection, independently of the lesion localization, demonstrating that NIe4-D-phe7-α-MSH may be effective and safe for the treatment of Hailey-Hailey disease.
Description: Analysis of molecular alterations in keratinocytes of HHD patients and treatment with a α-MSH-analogue compound.
URI: http://hdl.handle.net/10805/2561
Research interests: Applied and Basic research in Molecular Biology, Biochemistry, Genetic.
Skills short description: Highly experienced with immortalized mammalian cells, cloning and DNA manipulation, PCR and RT-PCR, Transfection, Western blot, Immunoprecipitation and pull-down assay.
Personal skills keywords: Reliable
Adaptable
careful
Indipendentt
Hardworking
Appears in PhD:MEDICINA MOLECOLARE

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