Project Summary Asthma is a serious health and economic concern worldwide. Recent studies indicate the role of vagal sensory neurons in the pathogenesis of asthma; however, the underlying molecular and cellular mechanisms are unclear. Recently we found that MrgprC11, a previously identified itch receptor in the skin nerves, is expressed in a subset of vagal sensory neurons innervating the airway. Bam8-22, a potent agonist of MrgprC11, induces cholinergic bronchoconstriction in WT mice, but not in knockout mice in which MrgprC11 was deleted. Administration of Bam8-22 can also enhance airway sensitivity to bronchoconstrictors in the absence of airway inflammation, suggesting the role of MrgprC11+ neurons in airway hyperresponsiveness. We have generated a BAC transgenic mouse line MrgprC11CreER to express inducible Cre DNA recombinase in MrgprC11+ neurons. In this proposal, we will use molecular, cellular, immunohistochemical and genetic approaches combined with a novel calcium imaging technique to elucidate the function of MrgprC11+ vagal sensory neurons in the airway and investigate their role in asthma. Aim 1 will focus on the anatomical analysis of the axonal innervation pattern of MrgprC11+ vagal sensory neurons using genetic labeling tools. In Aim 2, we will identify the endogenous/exogenous agonists for MrgprC11+ vagal sensory neurons to characterize the physiological properties of these neurons. In Aim 3, we will determine the contribution of MrgprC11+ vagal sensory neurons in a mouse allergic asthma model. We will test our hypothesis that MrgprC11+ vagal sensory neurons exhibit hypersensitivity in allergic airway inflammation and play a role in the development of airway hyperresponsiveness. These studies will advance our understanding of the neural basis underlying asthma symptoms and will have significant impact on the clinical treatment of asthma.