Optimizing Keratinocyte Calcium Signaling Enhances Differentiation in Aged Epidermis

Aged epidermis shows progressive defects in proliferation, differentiation and barrier formation, manifesting as eczematous dermatoses, xerosis, itch and increased susceptibility to contact dermatitis and infections. Previously, we found that defects in epidermal calcium signaling, transduced through the plasma membrane calcium receptor (CaSR), underlie intrinsic aging. In preliminary findings we show that CaSR expression decreases in aged epidermis and CaSR agonists rescue calcium signaling, E-cadherin reorganization, growth and migration in aged keratinocytes, epidermal equivalents and aged or CaSR-/- mice. Because burn pit pollution also causes premature skin aging (extrinsic skin aging) and is a focus of veteran health, we propose to determine what age-related transcriptional or epigenetic mechanisms drive intrinsic vs. extrinsic aging. We next will assess how increasing CaSR expression or function, using exogenous vitamin D or CaSR agonists, rescue intrinsic or extrinsic age-related epidermal defects. Finally, we will use these results to develop therapeutic approaches that ameliorate calcium signaling and differentiation/barrier defects in intrinsically aged mice or mice whose skin is prematurely aged due to particulate pollution. The overall hypothesis of this project is that the age-related decreases in calcium signaling dysregulate intrinsic and extrinsic keratinocyte differentiation and barrier homeostasis. The overall goal of this project is to normalize age-related epidermal defects by enhancing calcium signaling and CaSR expression/function.