Cutaneous opioid circuitry in skin inflammation and sensation

PROJECT SUMMARY/ABSTRACT Inflammatory skin diseases such as atopic dermatitis and hidradenitis suppurativa are associated with significant burdens of chronic itch and pain. Endogenous opioid peptides regulate these noxious sensations and have critical homeostatic functions. While opioid biology research has predominantly focused on pharmacology, much less is known about the endogenous opioid biology and circuits within the skin. My preliminary data has identified the cellular sources of the endogenous opioid enkephalin and its function in regulating skin inflammation and sensation. In this mentored career development plan, I aim to expand on my previous and preliminary work to fill the knowledge gaps in cutaneous opioid circuitry and function. In Aim 1, I propose to characterize the cutaneous sources of enkephalin and their somatosensory functions in homeostasis and after inflammation. I hypothesize that regulatory T cell-derived enkephalin will suppress allodynia, while keratinocyte-derived enkephalin will suppress itch after inflammation. Additionally, I have identified the localization of the preferred receptor for enkephalin, the d elta opioid receptor (δOR), and found that pharmacological or genetic inhibition of this receptor leads to height ened allodynia and itch. In Aim 2, I will develop RNA-sequencing and in vivo calcium imaging methods for skin- innervating sensory neurons to identify how δOR regulates sensory neuron identity and functional activity in response to cutaneous stimuli. Finally, in Aim 3, I will assess whether genetic or pharmacological modulation of the enkephalin-δOR circuit can influence cutaneous inflammation and itch in a murine dermatitis model. Under the guidance of Dr. Allan Basbaum, an authoritative expert in sensory neuroscience, and a committee of multidisciplinary scientific leaders, I will leverage my immunological expertise to further my long-term goal of becoming an independent physician-scientist. My scientific career will focus on defining the signaling interface between the immune and nervous systems in cutaneous inflammation and sensory perception. This proposal will enhance my skills in imaging, sequencing, sensory neuroscience and signaling, allowing me to identify new targets for alleviating skin disease. This five -year career development plan will provide comprehensive training in statistical analysis, scientific communication, laboratory management and leadership, laying the groundwork for my future role as an independent researcher contributing to our understanding of cutaneous biology.