Functional interrogation of sensory neurons in inflammation

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PROJECT SUMMARY: Chronic inflammatory diseases afflict millions of Americans and place devasting burdens on patient’s lives. Effective treatments for these disorders are lacking, partly because the multicellular interactions between bodily systems (e.g. the peripheral nervous and immune systems) that drive inflammation are poorly understood. For example, it is known that sensory neurons play context-dependent roles in a variety of inflammatory disorders by modulating the immune response. The specific neuronal subtypes and molecular mechanisms that contribute to this remain unclear. The overarching goal of my research is to unravel the precise mechanisms by which peripheral sensory neurons influence the pathogenesis of inflammatory diseases of the skin and visceral organs and how sensory neurons are in turn influenced by the immune system. A subtype of sensory neuron that detects itch (pruriceptors), expresses a number of receptors for pro-inflammatory and immunomodulatory molecules. Thus, these pruriceptors are attractive candidates for orchestrating multicellular interactions during inflammation. However, the role of these specific sensory neurons in inflammatory disease is unstudied as, until recently, the tools to precisely target these neurons were lacking. To bridge this gap in knowledge, this proposal will elucidate the contribution of pruriceptors to distinct inflammatory states. The proposed research will interrogate pruriceptor function using genetic and viral approaches in mouse models to selectively target and ablate these neurons and measure the effects of these manipulations on mouse models of inflammatory diseases. Specifically, I will test the hypothesis that pruriceptors, as polymodal sensors of aversive chemical, mechanical, and immune stimuli, drive hypersensitivity and local inflammatory responses in a context-specific manner. During the K99 phase, I will leverage my proven track record in studying neuroimmune interactions with innovative techniques I am learning to target and manipulate specific subsets of sensory neurons and ultimately map and elucidate multicellular circuits in inflammation. Aim 1 will establish th e contributions of pruriceptors to chronic itch-evoked skin inflammation by combining viral and genetic approaches to selectively ablate pruriceptors with behavioral, immunological, electrophysiological, and transcriptomic read- outs to understand how pruriceptors contribute to skin inflammation. As molecularly similar sensory neurons of unknown function also innervate the gut, Aim 2 will translate this approach to the study of gastrointestinal tract inflammation and gut function using a model of gastritis. I will dedicate part of the K99 phase to career development activities such as mentoring, presenting at conferences, and publishing research articles. A portion of both Aims will carry over into the independent R00 phase of the award. This proposal will provide fundamental insights into the multicellular interactions underlying chronic inflammatory disease from a neuron-focused perspective. Successfully executing this training plan with the help of The Scripps Research Institute will prepare me to lead an independent research program.