Asthma is a chronic pulmonary condition affecting 34.1 million Americans with an annual cost of $19.7 billion. Sensitization to fungi in the context of asthma presents a severe clinical scenario that is difficult to treat, accounting for a disproportionately large number of emergency center visits and hospitalizations. The long term goal of our research is to understand the beneficial and detrimental effects of eosinophils in the context of the allergic lung and fungal exposure. The objective of this application is to link recruitment and trafficking of eosinophils in the lung lumen to signaling by a neuropeptide called vasoactive intestinal peptide (VIP). Our central hypothesis is that VIP, through an autocrine mechanism, signals through its VPAC2 receptor to regulate recruitment (chemokinesis) and MMP9 production (invasion) of eosinophils, facilitating their entry to the lumen of the lung. This hypothesis is based on our previously published work showing a significant reduction of eosinophils in the lung lumen of VPAC2 deficient mice after fungal challenge. Defining the molecular mechanisms that guide eosinophil trafficking will provide targets to regulate these cells to help facilitate their potential benefits and limit their pathologic effects and is the ratonale for this work. We will test our central hypothesis with two specific aims. We will determine the extent to which: 1) VIP/VPAC2 autocrine signaling controls eosinophil egression into the pulmonary lumen and 2) VPAC2 signaling is necessary for MMP9 de novo expression in eosinophils.
These aims will utilize VPAC2 wild type (C57BL/6) and knockout mice in an inhalation model of Aspergillus fumigatus allergic asthma that was developed by our research team.
Aim one will provide evidence that an autocrine loop of VIP/VPAC2 activates a chemokenetic program in eosinophils critical for lung recruitment.
Aim two will establish a molecular mechanism for eosinophil invasion into lung lumen by restructuring the chromatin architecture to a permissive state at the MMP9 promoter inducing its expression and secretion. The innovation for this proposal is connecting neuropeptide signaling to explain eosinophilia in an in vivo fugal allergic asthma model to improve training of NDSU students in molecular (Dr. Dorsam) and whole-body modeling (Dr. Schuh) and through training collaborations hosted in the clinical laboratories of Dr. Hirohito Kita (eosinophil techniques, Mayo Clinic) and Dr. Sinisa Dovat (chromatin remodeling, Hershey Medical School).
The proposed research will define the molecular mechanisms that control eosinophilia in allergic fungal exposure and is expected to provide insight to enhance their beneficial effects, while limiting their pathological effects, in health and disease.It is relevant to public health and the mission of the National Institutes of Health in that it will provide not only understanding of fungal exposure but will also be used to train the scientists who will be charged with discovering the therapies and protocols that in the future will reduce human morbidity from fungal exposures in the context of asthma.
|Ghosh, Sumit; Samarasinghe, Amali E; Hoselton, Scott A et al. (2014) Hyaluronan deposition and co-localization with inflammatory cells and collagen in a murine model of fungal allergic asthma. Inflamm Res 63:475-84|