The role of IL17A and keratinocyte stem cells in human psoriasis.

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BACKGROUND: Psoriasis is a benign inflammatory immunological disorder characterized by hyperproliferation of the epidermis. The role of stem cell (SC) divisional behavior in the hyperproliferation of psoriasis has not been addressed previously. PRELIMINARY DATA: As part of our last completed Merit Review we provided evidence to show that while oncogenic hyperproliferation is associated with symmetric SC divisions (producing increased numbers of SCs), benign hyperproliferation is associated with increased asymmetric SC divisions (no change in SC number). In studies subsequent to the previous Merit, we showed that the increase in asymmetric SC divisions in psoriasis was interleukin 17A dependent (Charruyer et al, 2017). HYPOTHESES: in Aim 1 we hypothesize that the observed increase in SC divisions is due to an increase in actively cycling SCs rather than a change in cell cycle duration, and that the increase in progenitor transit amplifying cells (TACs) in the suprabasal layer is a downstream consequence of the change in SC behavior rather than an increase in 'rounds' of TAC divisions. In Aim 2 we hypothesize that genes associated with signaling pathways related to SC quiescence and to asymmetric SC division will be differentially expressed in the SCs of interleukin 17A versus vehicle-treated keratinocytes. SHORT TERM GOALS: In Aim 1 we will complete studies to fully elucidate how altered SC and TAC kinetics result in the acanthotic (thickened) epidermis of psoriasis. In Aim 2 we will determine the changes in gene pathways underlying the altered SC behavior; pathways associated with quiescence and asymmetric SC division, using RNAseq and then validate these genes/pathways as relevant for psoriasis and for keratinocyte SC self-renewal using normal and psoriasis human keratinocytes. LONG TERM GOALS: The studies of Aim 1 are designed to enable a relevant new mathematical modeling of psoriasis as a future goal. Aim 2 will elucidate molecular mechanisms underlying the alterations in Aim 1 and provide strategies for manipulation of SC divisional behavior. Along with better understanding hyperproliferative diseases, these studies will move us closer to important therapeutic goals: to target quiescent/dormant cancer cells that escape conventional therapies, to decrease SC quiescence/ increase symmetric SC divisions to aid wound healing, and to restore homeostasis between the balance of asymmetric and symmetric SC divisions in the treatment of psoriasis and other hyperproliferative diseases.