Transcriptional Programming of Asthma Related Pathology in Respiratory Epithelia

描述(由申请人提供)：本次续签申请寻求资金，以确定一个转录网络，该网络确定AEC分化、杯状细胞化生/增殖以及与哮喘、其他慢性肺部疾病和鼻病毒急性病毒感染的发病机制有关的炎症。这项应用基于新的数据，证明了拟议的转录网络的关键作用，该网络以ETS家族成员SPDEF(SAM指向结构域ETS样因子)为中心，调节杯状细胞的分化和肺部的炎症过程。我们的初步数据表明，AEC在传导气道中的分化是由一种细胞内源性转录程序介导的，其中SPDEF和FOXA家族成员以及TTF-1(甲状腺转录因子-1，又名Nkx2.1)发挥着重要作用。初步数据支持SPDEF促进黏液细胞化生、嗜酸性趋化因子和TH2细胞因子表达的概念，以应对过敏原和鼻病毒感染。这项应用将利用SPDEF缺失或表达的转基因小鼠模型、生物信息学、人支气管上皮细胞(HBECs)的体外培养和生物化学来确定SPDEF控制粘液化生和天然免疫的机制。目的1研究鼻病毒和空气变应原诱导的黏液化生过程中转录因子SPDEF在转录和转录后水平的调控机制。将确定控制其调节和功能的机制。目的2验证SPDEF调节黏液细胞分化、先天免疫和呼吸道上皮炎症关键基因转录的假说，确定AECs的转录靶点。目的3确定SPDEF在小鼠体内模型中的生理和炎症后果，确定该网络在病毒感染和TH2刺激下对肺生理、炎症反应和组织重塑的影响。目前的应用表明，我的实验室对健康和疾病中进行呼吸道上皮细胞分化的转录控制越来越感兴趣。这些研究将为深入了解糖尿病的发病机制提供依据。 与哮喘、COPD和急性感染相关的粘液细胞化生和过度产生通常会使这些疾病复杂化，为制定新的战略来诊断和治疗慢性呼吸道疾病提供了基础，这些疾病是全球发病率和死亡率的常见原因。

DESCRIPTION (provided by applicant): This renewal application seeks funding to define a transcriptional network that determines AEC differentiation, goblet cell metaplasia/hyperplasia, and inflammation related to the pathogenesis of asthma, other chronic pulmonary disorders, and acute viral infection by rhinovirus. The application is based on novel data demonstrating the critical roles of the proposed transcriptional network that is centered on an Ets family member, SPDEF (SAM pointed domain ets-like factor) that regulates goblet cell differentiation and inflammatory processes in the lung. Our preliminary data demonstrate that differentiation of AECs in conducting airways is mediated by a cell intrinsic transcriptional program in which SPDEF and FOXA family members and TTF-1 (thyroid transcription factor-1, aka Nkx2.1) play fundamental roles. Preliminary data support the concept that Spdef drives mucus cell metaplasia, eosinophilic chemokine, and TH2 cytokine expression from AECs in response to allergens and rhinoviral infection. The application will utilize transgenic mouse models in which Spdef is deleted or expressed; bioinformatics, in vitro cultures of human bronchial epithelial cell (HBECs), and biochemistry to determine mechanisms by which SPDEF controls mucus metaplasia and innate immunity. Aim 1 will identify the mechanisms by which the transcription factor SPDEF is regulated at transcriptional and post-transcriptional levels during mucus metaplasia induced by rhinovirus and aeroallergen exposure. Mechanisms controlling its regulation and function will be identified. Aim 2 will test the hypothesis that SPDEF regulates transcription of genes critical for mucus cell differentiation, innate immunity, and inflammation i the respiratory epithelium, identifying transcriptional targets in AECs. Aim 3 will identify physiological and inflammatory consequences of SPDEF in mouse models in vivo, identifying the effects of the network on pulmonary physiology, inflammatory responses, and tissue remodeling during viral infection and TH2 stimulation. The present application represents my laboratory's increasing interest in the transcriptional control of conducting airway epithelial cel differentiation in health and disease. These studies will provide insights into the pathogenesis of mucus cell metaplasia and hyperproduction associated with asthma, COPD, and acute infections that commonly complicate these disorders, providing the basis for the development of new strategies to diagnose and treat chronic respiratory diseases that are common causes of morbidity and mortality world- wide.