The continued objective of this proposal is to determine the critical role of PI3K/Akt/mTOR in psoriasis pathogenesis and to develop delphinidin for the management of psoriasis, a common chronic inflammatory skin disorder that affects 125 million people worldwide. Although psoriasis is not life- threatening, it presents disabling physical and psychosocial discomfort and global disease burden associated with psoriatic arthritis and cardiovascular disease risks. Being multifactorial, it is unlikely that hiting a single target will significantly benefit patients, thus the need for developing effective mechanism and target-based agents to treat psoriasis. Among the many signaling networks implicated in psoriasis disease, the PI3K/AKT/mTOR pathway has emerged as clinically relevant target, as it may cooperatively promote psoriasis. Using retrospective human psoriatic and imiquimod (IMQ)-induced murine psoriasis-like skin lesional tissues we observed activation of AKT/mTOR signaling compared to matched controls. These observations form the basis of our proposal that simultaneous targeting of PI3K/Akt/mTOR may be an effective approach for treating psoriasis. In line with this hypothesis and in our pursuit for non-toxic natural agents endowed with pro- differentiation and anti-inflammatory properties in skin, we recently made some novel and exciting observations with delphinidin. Delphinidin treatment of human keratinocytes pre-stimulated with/without IL-22 inhibited PI3K, Akt and mTOR activation. Further competitive binding and in silico docking analyses revealed that delphindin physically interacts with the PI3K, mTOR and p70S6K kinases with binding energy of -7 to -8.9Kcal/mol range, In this application, we propose to take advantage of the multi-pronged ability of delphinidin and is designed to: 1) Examine the involvement of PI3K/Akt/mTOR and secondary signaling in psoriasis pathogenesis; 2) Investigate the efficacy of delphinidin using (i) in-vitro 2D cultures, i) 3D reconstituted human skin models of psoriasis, and iii) in-vivo IMQ-induced Balbc and TPA-induced K14/VEGF transgenic murine psoriasiform models that recapitulates many features of human psoriasis. A successful completion of this proposal may result in our understanding of mechanism of psoriasis pathogenesis via dissecting interaction of PI3K/AKT/mTOR and the development of delphindin as a novel agent against proliferative keratinizing disorders, including psoriasis.

Public Health Relevance

Psoriasis is a common chronic inflammatory skin disorder that affects 125 million people worldwide. Although psoriasis is not life-threatening, it presents disabling physical and psychosocial discomfort. These studies proposed are designed to investigate the mechanism of PI3K/Akt/mTOR interaction and to develop delphinidin, a dietary anthocyanidin for the management of psoriasis. A successful completion of studies in this proposal will contribute to our understanding of mechanism of psoriasis pathogenesis and the development of delphinidin as an agent against proliferative disorders, including psoriasis.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Cibotti, Ricardo
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University of Wisconsin Madison
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United States
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