A mechanistic investigation of SerpinB3 and its role in psoriasis - SUMMARY Psoriasis vulgaris (or plaque psoriasis) is a chronic skin disease affecting 2-3% of the worldwide population and the most common manifestation of psoriasis. Though psoriasis has a low mortality rate, it is strongly associated with several potentially deadly comorbidities, including several cancers, and psoriasis patients experience significantly elevated levels of depression, anxiety, and completed suicide. There is a recognized unmet need for new treatments against moderate-to-severe psoriasis due to the development of treatment inefficacy and high costs for more effective, second-line treatments. Despite substantial progress in characterizing the molecular mechanisms of psoriasis, the molecular events stimulating the initiation and pathogenesis of plaque psoriasis remain unknown. While inflammation, particularly Th17-driven, has gained attention, there is significant ongoing debate about the role of both immune dysregulation and keratinocyte dysfunction in the onset and progression of psoriatic disease, and investigation of druggable factors from keratinocytes is warranted. SerpinB3 is a keratinocyte-expressed serine protease inhibitor with substantial evidence for a potential mechanistic role in psoriasis. SerpinB3 is highly upregulated in the skin of patients with psoriasis and the misprocessed form of SerpinB3, Pso p27, is the dominant autoantigen found in the protein mass of psoriatic plaque scales. However, despite robust and suggestive evidence no studies investigating SerpinB3 as the initiating, etiological agent in the pathogenesis of psoriasis have been reported. This proposal will explore the hypothesis that misprocessing of SerpinB3 is the initiating agent of psoriasis in three aims. Aim 1 will focus on mechanistic investigation of SerpinB3 dysregulation in vitro using cell-based studies to understand how SerpinB3 may traffic from keratinocytes to mast cells, which evidences suggests produce Pso p27 despite do not endogenously expressing SerpinB3, as well as a role for Pso p27 in Th17-driven inflammation. Aim 2 will evaluate the role of mouse ortholog Serpinb3a in the pathogenesis of psoriasis with the imiquimod-induced psoriasis model in wildtype, Serpinb3a-deficient, and mast cell-deficient mice. Further, an investigation of whether Pso p27 is the etiological agent of psoriasis will be undertaken by direct delivery of immune complexes into the skin of wildtype, mast cell-deficient, and IL-17-deficient mice with no other stimulus. Aim 3 will explore whether SerpinB3 is a druggable target for the treatment of psoriasis at the transcriptional, translational, and post- translational levels in both human explanted culture models and mouse models. The success of the research is supported by a strong, diverse team with complementary scientific expertise in serpin biology, drug delivery, dermatology, and pathology. This proposal, a new direction for an early-stage investigator PI with established expertise in serpin biology and relevant techniques, will leverage the innovative and scientifically robust environment at Arizona State University and neighboring institutions to develop a paradigm-shifting molecular mechanism of disease in psoriasis with potential for therapeutic targeting with a solid path to clinical translation.
