Signaling Memory in Chronic Asthma

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In chronic asthma the fundamental pathologic process persists in a self-perpetuated manner. The mechanism of this self-sustained process is unknown. We have established a murine model of chronic experimental asthma, wherein the characteristic pathologic process of asthma continues in the absence of the inciting allergens. Based upon a phosphoprotein screen of the lung tissue from this model we hypothesize that the ERK1/2 signaling pathway induces a self-sustaining signaling network that functions as a system memory. Self-perpetuated activation of this signaling pathway drives the biological processes that sustain eosinophilic inflammation, mucus production, airway hyperreactivity and remodeling in asthma. The objective of this project is to delineate the molecular mechanism of the memory-like function of ERK1/2 in chronic asthma. Specific aim #1 will address the role of Sprouty proteins in sustained ERK activation. We will study the importance of a hitherto unknown interaction of Sprouty with Src family kinases. We will study the effect recombinant Sprouty proteins on Src family kinase activation. Further, we will examine the relative resistance 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 cytosolic deactivating processes. We will assess the role of autocrine/paracrine stimulation of proinflammatory cytokines such as IL-13 in sustaining ERK1/2 activation. Specific aim #3 will assess the biological relevance of ERK1/2 as a system memory. We will apply knockout and transgenic approaches, biologies and pharmacological agents to examine the relevance of ERK1/2-based memory for chronic asthma. Specific aim #4 is a collaborative aim. In collaboration with Project 2 we will determine the importance of CD8+BLT1+ T cells as the source of ERK1/2 signaling. Further, in collaboration with Project 1 we will study steroid 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 development and functioning of a disease-related memory. A molecular understanding of this process has implications for chronic illnesses beyond asthma.