PROJECT SUMMARY/ABSTRACT Skin sensory neurons are essential for detecting noxious environmental threats and inducing pain and itch. Neurotransmitters released from skin nerve endings not only mediate these forms of neural sensation but also drive or regulate inflammatory responses. Several members of the Mas-related G-protein coupled receptor (MRGPR) family are expressed in sensory neurons and thought to play a crucial role in neuroimmune interactions. It remains unclear, however, which MRGPRs serve to transduce itch- and inflammation-inducing signals in atopic dermatitis and other allergic skin diseases. Evidence from our published and preliminary studies points to mouse MrgprA1 and its human counterpart, MRGPRX2, as the physiologically relevant receptor for substance P (SP), a neuropeptide with a well-established role in itch and neurogenic inflammation. This finding challenged the widely held notion that SP stimulated dorsal root ganglion neurons via the neurokinin-1 receptor and prompted us to investigate whether MrgprA1/MRGPRX2 serves as a key mediator of neuroimmune interactions and contributes to atopic dermatitis (AD) where itch and inflammation manifest as major pathophysiologic features. The proposed research will test the hypothesis that MrgprA1/MRGPRX2 expressed on sensory nerves serves as the SP receptor and plays a crucial role in itch and allergic skin inflammation. For this investigation, a newly developed mouse model of skin inflammation will be used that closely recapitulates AD pathophysiology and visualizes peripheral nerve fiber dynamism with exquisite clarity. We will pursue the following specific aims during the project period: to elucidate the role of MrgprA1 in neuronal SP sensing and inflammation-associated itch (Aim 1); to determine the contribution of Mrgpr-expressing sensory neurons and MrgprA1 signaling to shaping the skin immune microenvironment and driving allergic skin inflammation (Aim 2); and to assess the potential of antagonizing MrgprA1 action and MrgprA1+ nerve dynamism for AD treatment (Aim 3). The proposed research tests novel ideas and seeks to close knowledge gaps in neuroscience, immunology, and skin biology. If successful, this research project will establish new molecular mechanisms by which neuronal Mrgpr signaling mediates neuroimmune interactions and contributes to AD and other allergic skin diseases. This knowledge will translate into effective clinical strategies for the treatment of itch and skin inflammation.