Signaling Memory in Chronic Asthma

在慢性哮喘中，基本的病理过程以自我延续的方式持续存在。这个 这种自我维持的过程的机制尚不清楚。我们已经建立了一种慢性阻塞性肺疾病小鼠模型 实验性哮喘，其中哮喘特有的病理过程在缺乏 刺激性过敏原。根据这个模型的肺组织的磷蛋白筛查，我们 假设ERK1/2信号通路诱导一个自我维持的信号网络，其功能是 系统内存。这一信号通路的自我持续激活推动了生物过程， 维持哮喘患者的嗜酸性炎症、粘液产生、呼吸道高反应性和重塑。这个 本课题的目的是阐明ERK1/2在脑内记忆功能中的分子机制。 慢性哮喘。 具体目标#1将阐述芽胞蛋白在持续的ERK激活中的作用。我们会研究 Sprouty与Src家族激酶相互作用的重要性。我们将研究这一影响 重组芽孢蛋白对Src家族蛋白激活的影响。此外，我们将检查相关的 磷酸化ERK1/2对磷酸酶的抗性。《特殊目标2》将检验这样一个假设，即记忆- 相关的ERK1/2池被保存在内体隔室，这使得它能够逃脱胞浆 停用进程。我们将评估自分泌/旁分泌刺激促炎症的作用。 IL-13等细胞因子在维持ERK1/2激活中的作用具体目标#3将评估生物相关性 ERK1/2作为系统存储器。我们将应用基因敲除和转基因方法、生物学和 检查ERK1/2为基础的记忆与慢性哮喘的相关性的药理学药物。特定的 目标4是一个协作性目标。在与项目2的合作中，我们将确定 CD8+BLT1+T细胞作为ERK1/2信号的来源。此外，我们将与项目1合作研究 我们的慢性哮喘模型中的类固醇抵抗，并检查ERK1/2是否在这一过程中起作用。 我们将使用分子、转基因和基因敲除方法来解决这些问题。 拟议的研究很重要，因为它解决了关于发展的一个基本问题。 以及疾病相关记忆的功能。对这一过程的分子理解对 哮喘以外的慢性病。

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.