טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentNousbeck Janna
SubjectPharmacogenetics of Psoriasis
DepartmentDepartment of Medicine
Supervisors Mr. Eli Sprecher
Professor Adi Salzberg
Full Thesis textFull thesis text - English Version


Abstract

Psoriasis is a chronic inflammatory skin disease affecting 1-3% of the general population. Phototherapy is considered as one of the most efficient and safest therapeutic modalities to treat psoriasis. However, the response to phototherapy is variable, costly, with exposure of the skin to UV-light and the long period of time needed to determine treatment success. Therefore parameters capable of predicting response to phototherapy have long been sought. Pharmacogenetics aims to elucidate the genetic basis for interindividual differences in response to treatment. The hypothesis of our study was that the combined use of the main approaches of pharmacogenetics may advance the management and possibly reveal new therapeutic options for multifactorial diseases like psoriasis. Recently, a global gene expression study revealed that insulin-like growth factor (IGF)-binding protein IGFBP7 is down-regulated in the psoriatic epidermis, with UVB phototherapy restoring its expression to normal. These data suggest that IGFBP7 may be involved in the pathogenesis of psoriasis. IGFBP7 has been shown in cancer cells to function as a potent tumor suppressor gene, down-regulating proliferation as well as promoting differentiation and apoptosis. These processes are impaired in psoriasis. Therefore, we reasoned that the characterization of IGFBP7 role in keratinocytes may reveal IGFBP7 contribution to the pathogenesis of psoriasis.

To achieve this aim, we used human HaCaT keratinocyte lines and human primary keratinocytes that are studied in monolayer; an in vitro system where human keratinocytes are studied in three dimensional skin equivalents and psoriatic animal models. To model IGFBP7 downregulation in vitro, we used RNAi techniques in HaCaT cells and in primary human keratinocytes. Downregulation of IGFBP7 was found to enhance keratinocyte proliferation, decrease keratinocyte susceptibility to TNF-α-induced apoptosis and block calcium-induced differentiation of human keratinocytes. Recombinant IGFBP7 was found to significantly inhibit keratinocyte proliferation. Downregulation of IGFBP7 was found to activate the MAPK pathway, which has previously been shown to be involved in the pathophysiology of psoriasis. The knockdown of IGFBP7 in three-dimensional skin equivalents led to changes highly reminiscent of psoriasis including hyperkeratosis, parakeratosis and hypogranulosis. Taken altogether, we concluded that IGFBP7 is involved in the pathogenesis of psoriasis. These data suggest that IGFBP7 may treat psoriasis and related hyperproliferative skin diseases. To substantiate this hypothesis, we used an animal model of human psoriasis. Recombinant IGFBP7 cured most affected animals.

In conclusion, our data provide evidence for IGFBP7 critical contribution to the pathogenesis of psoriasis and its potential therapeutic relevance for the disease treatment.