KAST

The elderly population is particularly sensitive to temperature changes, since aging weakens the thermoregulatory mechanisms leading to a strong vulnerability to sustained heat waves. With climate change, the incidence, duration and severity of these heat waves are expected to increase. It is therefore crucial to improve our understanding of the impact of age progression on the physiological mechanisms of thermoregulation in order to reduce health risks during heat stress in elderly. Historically, sensory nerve endings passing through the epidermis were thought to be the exclusive transducers for temperature detection and consequently, thermoregulation. However, the epidermal keratinocytes also act as a cutaneous sensory hub, able to detect thermal changes. Therefore, the question of how the thermosensitive receptors of epidermal keratinocytes, especially TRPV3, communicate with skin vessels in the deep layers of the dermis remains to be resolved. We hypothesize that the TRPV3 localized on the keratinocytes has an important role in temperature sensing defects in older individuals. Our KAST project aims to clarify the impact of aging on 1) heat-sensitive TRPV3 channels expressed on epidermal keratinocytes, 2) their interactions with intra-epidermal nerve endings, mainly peptidergic fibers, and 3) the factors released by the keratinocytes following TRPV3 activation that have the potential to be involved in age-related vascular thermoregulatory disorders. Putting keratinocytes at the centre of the dysregulation of homeostatic equilibrium leading to impairments of the vascular thermoregulation in elderly is novel and timely. The recent discovery of synaptic like structures between epidermal keratinocytes and sensory neurons is a paradigm shift leading to the consideration of the whole epidermis as a sensory epithelium. To reach our important goal, the KAST project will apply a multimodal approach, with 3 public partners specifically chosen for their complementary expertise in in vivo vascular evaluation, ex vivo analysis of human and mouse skin biopsies, and in vitro experiments with mono cell cultures and co-cultures of keratinocytes and sensory neurons in a full 2D human model, which represents a unique opportunity to reduce animal experimentation, whilst being clinically relevant.