Sensory neuronal mechanism for development of house dust mite induced airway hyperreactivity - Asthma is the most common chronic inflammatory disease of the airways, affecting 24.6 million people in the US and almost 500 million worldwide. Asthmatic patients have three main characteristics: airway resistance due to narrowing of the airways, lung inflammation, and airway hyperreactivity (AHR). AHR is the excessive and inappropriate response of the airways to a bronchospastic/irritant stimulus. Current asthma medications target airway blockage and inflammation, but none adequately treat AHR. AHR is the cause of most symptoms and exacerbations of asthma and persists even if the chronic inflammation in the lungs is cleared. There is a significant gap in our understanding of the mechanisms underlying the development of AHR. House dust mites (HDM), a common trigger of asthma, cause the development of AHR and evidence suggests this is independent of IgE-mediated atopy and we found this AHR is dependent on nociceptive sensory nerves innervating the airways. However, the mechanisms and specific sensory neve populations responsible for HDM-mediated AHR are poorly understood. The long-term goal of this proposal is to define the neural mechanisms that are triggered by HDM by activating the airway afferents leading to the development of AHR, so that we can develop targeted therapies. The objective of the study is to identify the specific nerve subtype and the signaling mechanism triggered by HDM activation of the airway vagal afferents and determine the mechanism by which AHR eventually develops. The central hypothesis is that HDM component proteases cause PAR1 dependent activation, via TRPV1 and Ano1 ion channels, of vagal C-fibers which leads to the development of HDM-induced AHR. To address the hypothesis, we have three specific aims: Aim 1: Determine the protease-mediated mechanism of HDM-evoked airway afferent activation and AHR. Aim 2: Determine the afferent effectors underlying HDM- mediated afferent activation and AHR. Determine the contribution of chronic activation and phenotypic changes in afferents to HDM-evoked AHR. We hypothesize that the development of HDM-induced AHR in mice is due to the activation of the TRPV1 and Ano1 ion channels, expressed on airway vagal afferents, downstream of PAR1 activation. The rationale of this proposal is that once we understand the mechanisms, we will be able to treat AHR. This R01 will be significant because it this proposal will be the first to define the afferent subset and the molecular mechanisms necessary for triggering AHR in a translationally relevant HDM mouse model of AHR. This R01 research proposal is innovative because it (1) investigates the initial responses to HDM that are sufficient to cause AHR independent of inflammation, (2) hypothesis that HDM components directly activate naïve airway afferents which then lead to AHR, is innovative. The outcomes of this study will provide a novel rationale for pharmacological or electroceutical therapies that target airway afferent nerves hence treating the condition, for the first time, of AHR in clinical studies.
