In chronic asthma the fundamental pathologic process persists in a self-perpetuated manner. Themechanism of this self-sustained process is unknown. We have established a murine model of chronicexperimental asthma, wherein the characteristic pathologic process of asthma continues in the absence ofthe inciting allergens. Based upon a phosphoprotein screen of the lung tissue from this model wehypothesize that the ERK1/2 signaling pathway induces a self-sustaining signaling network that functions asa system memory. Self-perpetuated activation of this signaling pathway drives the biological processes thatsustain eosinophilic inflammation, mucus production, airway hyperreactivity and remodeling in asthma. Theobjective of this project is to delineate the molecular mechanism of the memory-like function of ERK1/2 inchronic asthma.
Specific aim #1 will address the role of Sprouty proteins in sustained ERK activation. We will study theimportance of a hitherto unknown interaction of Sprouty with Src family kinases. We will study the effectrecombinant Sprouty proteins on Src family kinase activation. Further, we will examine the relativeresistance of phospho-ERK1/2 to phosphatases.
Specific aim #2 will test the hypothesis that the memory-related ERK1/2 pool is preserved in the endosomal compartment, which allows it to escape the cytosolicdeactivating processes. We will assess the role of autocrine/paracrine stimulation of proinflammatorycytokines such as IL-13 in sustaining ERK1/2 activation.
Specific aim #3 will assess the biological relevanceof ERK1/2 as a system memory. We will apply knockout and transgenic approaches, biologies andpharmacological agents to examine the relevance of ERK1/2-based memory for chronic asthma.
Specificaim #4 is a collaborative aim. In collaboration with Project 2 we will determine the importance ofCD8+BLT1+ T cells as the source of ERK1/2 signaling. Further, in collaboration with Project 1 we will studysteroid resistance in our chronic asthma model and examine whether ERK1/2 contributes to this process.We will employ molecular, transgenic and knockout approaches to address these problems.The proposed research is important because it addresses a fundamental question about the developmentand functioning of a disease-related memory. A molecular understanding of this process has implications forchronic illnesses beyond asthma.
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