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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR059742-10
Application #
9751767
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Cibotti, Ricardo
Project Start
2010-06-01
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Wisconsin Madison
Department
Dermatology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Chamcheu, Jean Christopher; Siddiqui, Imtiaz A; Adhami, Vaqar M et al. (2018) Chitosan-based nanoformulated (-)-epigallocatechin-3-gallate (EGCG) modulates human keratinocyte-induced responses and alleviates imiquimod-induced murine psoriasiform dermatitis. Int J Nanomedicine 13:4189-4206
Syed, Deeba N; Aljohani, Ahmed; Waseem, Durdana et al. (2018) Ousting RAGE in melanoma: A viable therapeutic target? Semin Cancer Biol 49:20-28
Khan, Mohammad Imran; Rath, Suvasmita; Adhami, Vaqar Mustafa et al. (2018) Hypoxia driven glycation: Mechanisms and therapeutic opportunities. Semin Cancer Biol 49:75-82
Chamcheu, Jean Christopher; Adhami, Vaqar M; Esnault, Stephane et al. (2017) Dual Inhibition of PI3K/Akt and mTOR by the Dietary Antioxidant, Delphinidin, Ameliorates Psoriatic Features In Vitro and in an Imiquimod-Induced Psoriasis-Like Disease in Mice. Antioxid Redox Signal 26:49-69
Chamcheu, Jean Christopher; Siddiqui, Imtiaz A; Mukhtar, Hasan (2016) Chemical chaperone therapy, a new strategy for genetic skin fragility disorders. Exp Dermatol 25:183-4
Syed, Deeba N; Adhami, Vaqar Mustafa; Khan, Naghma et al. (2016) Exploring the molecular targets of dietary flavonoid fisetin in cancer. Semin Cancer Biol 40-41:130-140
Chamcheu, Jean Christopher; Chaves-Rodriquez, Maria-Ines; Adhami, Vaqar M et al. (2016) Upregulation of PI3K/AKT/mTOR, FABP5 and PPAR?/? in Human Psoriasis and Imiquimod-induced Murine Psoriasiform Dermatitis Model. Acta Derm Venereol 96:854-6
Chamcheu, Jean Christopher; Pal, Harish C; Siddiqui, Imtiaz A et al. (2015) Prodifferentiation, anti-inflammatory and antiproliferative effects of delphinidin, a dietary anthocyanidin, in a full-thickness three-dimensional reconstituted human skin model of psoriasis. Skin Pharmacol Physiol 28:177-88
Pal, H C; Chamcheu, J C; Adhami, V M et al. (2015) Topical application of delphinidin reduces psoriasiform lesions in the flaky skin mouse model by inducing epidermal differentiation and inhibiting inflammation. Br J Dermatol 172:354-64
Syed, Deeba N; Chamcheu, Jean-Christopher; Khan, Mohammad Imran et al. (2014) Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: findings from 3-D melanoma skin equivalents and computational modeling. Biochem Pharmacol 89:349-60

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