Transcriptional Programming of Asthma Related Pathology in Respiratory Epithelia

描述（由申请人提供）：本更新申请寻求资金来定义一个转录网络，该转录网络决定AEC分化、杯状细胞化生/增生，以及与哮喘、其他慢性肺部疾病和鼻病毒急性病毒感染发病机制相关的炎症。该申请是基于新的数据，证明了以Ets家族成员SPDEF （SAM点结构域Ets样因子）为中心的转录网络的关键作用，该转录网络调节了杯状细胞分化和肺部炎症过程。我们的初步数据表明，传导气道中aec的分化是由细胞内在转录程序介导的，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）起着重要作用。初步数据支持Spdef驱动aec对过敏原和鼻病毒感染反应的粘液细胞化生、嗜酸性趋化因子和TH2细胞因子表达的概念。该申请将利用Spdef被删除或表达的转基因小鼠模型；通过生物信息学、人支气管上皮细胞（HBECs）体外培养和生物化学来确定SPDEF控制粘液化生和先天免疫的机制。目的1将确定在鼻病毒和空气过敏原暴露诱导的粘液化生过程中转录因子SPDEF在转录和转录后水平调控的机制。将确定控制其调节和功能的机制。目的2将验证SPDEF调节黏液细胞分化、先天免疫和呼吸上皮炎症的关键基因转录的假设，确定aec中的转录靶点。Aim 3将在小鼠体内模型中确定SPDEF的生理和炎症后果，确定该网络在病毒感染和TH2刺激期间对肺生理、炎症反应和组织重塑的影响。目前的应用代表了我的实验室对健康和疾病中传导气道上皮细胞分化的转录控制越来越感兴趣。这些研究将有助于深入了解

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.