Epithelial Barrier Programs in Asthma and Allergic Disease

哮喘和过敏性疾病的上皮屏障计划

• 批准号: 9327814
• 负责人: Michael J Holtzman
• 金额: $ 25万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327814
• 关键词: Address; Adult; Allergic Disease; Antiviral Agents; Asthma; Atopic Dermatitis; Autophagocytosis; Biological; Cell model; Cell physiology; Cells; Cellular biology; Child; Data Analyses; Defect; Development; Diagnosis; Disease; Epithelial; Epithelial Cells; Extrinsic asthma; Future; Goals; Health; Human; Hypersensitivity; Injury; Interferons; Intestines; Lead; Mediating; Metaplasia; Modeling; Molecular; Molecular Weight; Monitor; Mucous body substance; Pathogenesis; Pathway interactions; Process; Production; Proteins; Role; Sampling; Signal Pathway; Skin; System; TSLP gene; Therapeutic; Translating; Viral; Virus Diseases; airway inflammation; base; clinical biomarkers; human data; human subject; improved; mouse model; novel; prevent; programs; tissue processing

DESCRIPTION (provided by applicant): The overall goal of this AADCRC proposal is to define the role of the epithelial cell barrier in the pathogenesis of asthma and allergic disease and to use that information to prevent this type of disease. We combine expertise in airway as well as gut and skin epithelial cell biology, and we use cell and mouse models with high fidelity to directly translate our findings to humans. The AADRC therefore consists of three interrelated Projects that ask, first, how airway epithelial cells mediate effective antiviral defense under one condition but asthma under another (Project 1), second, how airway epithelial cells remodel towards an overabundance of mucous cells in post-viral and allergic asthma (Project 2), and third, how epithelial injury in the skin triggers the march from atopic dermatitis to asthma (Project 3). Each project addresses the respective question with a novel but overlapping molecular approach to mechanism and takes advantage of a breakthrough discovery to set a new scientific paradigm for the system under study. Thus, Project 1 unravels a new IFN signaling pathway that offers improved protection against viral infection and post-viral asthma and is specific to the airway epithelial cell barrier; Project 2 dissects a new pathway for autophagy proteins to support proper mucous cell function and prevent mucous cell metaplasia in the airway in a manner reminiscent of the intestinal epithelial barrier; and Project 3 defines a new TSLP production and secretion pathway that drives airway inflammation based on its expression in the skin epithelial barrier. Each Project is constructed so that the first aim will establish a basic pathogenic mechanism using cell and mouse models that are shared among projects and supported by the Cores for tissue and cell processing (Core C) and mouse models (Core D). In turn, each Project will conduct a second aim to validate and translate its findings using samples from children and adults with asthma and/or atopic dermatitis supplied by the Core for human subjects and data analysis (Core B). Sharing samples and overlapping scientific goals among projects create a synergistic program that can be coordinated by a common Administrative Core (Core A). Project and Core interactions are based on the overall principle that each Project begins with molecular hypothesis building in cell and mouse models and translates findings from these models to studies of humans with asthma and/or allergy. In each project, we aim to validate a clinically useful biomarker of the disease process and lay the groundwork for the future development of biological and/or small molecular weight compounds that might influence the process as a therapeutic strategy.

描述（由申请人提供）：该 AADCRC 提案的总体目标是确定上皮细胞屏障在哮喘和过敏性疾病发病机制中的作用，并利用该信息来预防此类疾病。我们结合了气道以及肠道和皮肤上皮细胞生物学方面的专业知识，并使用高保真度的细胞和小鼠模型将我们的发现直接转化为人类。因此，AADRC 由三个相互关联的项目组成，第一，气道上皮细胞如何在一种情况下介导有效的抗病毒防御，但在另一种情况下介导哮喘（项目 1），第二，气道上皮细胞如何重塑，导致病毒后和过敏性哮喘中粘液细胞过多（项目 2），第三，皮肤上皮损伤如何引发从特应性皮炎到过敏性皮炎的进展。 哮喘（项目 3）。每个项目都通过新颖但重叠的分子机制方法解决各自的问题，并利用突破性发现为所研究的系统设定新的科学范式。因此，项目 1 揭示了一种新的 IFN 信号传导途径，该途径可针对病毒感染和病毒后哮喘提供更好的保护，并且对气道上皮细胞屏障具有特异性；项目 2 剖析了自噬蛋白的新途径，以支持适当的粘液细胞功能并以类似于肠上皮屏障的方式防止气道中的粘液细胞化生；项目 3 定义了一种新的 TSLP 产生和分泌途径，根据其在皮肤上皮屏障中的表达来驱动气道炎症。每个项目的构建都是为了第一个目标是使用细胞和小鼠模型建立基本的致病机制，这些模型在项目之间共享并得到组织和细胞处理核心（核心 C）和小鼠模型（核心 D）的支持。反过来，每个项目将实施第二个目标，即使用人体受试者和数据分析核心（核心 B）提供的患有哮喘和/或特应性皮炎的儿童和成人样本来验证和转化其研究结果。项目之间共享样本和重叠的科学目标创建了一个可以由共同管理核心（核心 A）协调的协同计划。项目和核心相互作用基于以下总体原则：每个项目都从在细胞和小鼠模型中建立分子假设开始，并将这些模型的发现转化为对患有哮喘和/或过敏的人类的研究。在每个项目中，我们的目标是验证疾病过程的临床有用的生物标志物，并为未来开发可能影响疾病过程的生物和/或小分子量化合物作为治疗策略奠定基础。

项目成果

Tissue-dependent consequences of Apc inactivation on proliferation and differentiation of ciliated cell progenitors via Wnt and notch signaling.

• DOI: 10.1371/journal.pone.0062215
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Li A;Chan B;Felix JC;Xing Y;Li M;Brody SL;Borok Z;Li C;Minoo P
• 通讯作者: Minoo P

Respiratory Syncytial Virus whole-genome sequencing identifies convergent evolution of sequence duplication in the C-terminus of the G gene.

• DOI: 10.1038/srep26311
• 发表时间: 2016-05-23
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Schobel SA;Stucker KM;Moore ML;Anderson LJ;Larkin EK;Shankar J;Bera J;Puri V;Shilts MH;Rosas-Salazar C;Halpin RA;Fedorova N;Shrivastava S;Stockwell TB;Peebles RS;Hartert TV;Das SR
• 通讯作者: Das SR

STAT1 modification improves therapeutic effects of interferons on lung cancer cells.

STAT1修饰提高干扰素对肺癌细胞的治疗效果

• DOI: 10.1186/s12967-015-0656-0
• 发表时间: 2015-09-08
• 期刊: Journal of translational medicine
• 影响因子: 7.4
• 作者: Chen J;Zhao J;Chen L;Dong N;Ying Z;Cai Z;Ji D;Zhang Y;Dong L;Li Y;Jiang L;Holtzman MJ;Chen C
• 通讯作者: Chen C

Antiviral IFN-γ responses of monocytes at birth predict respiratory tract illness in the first year of life.

• DOI: 10.1016/j.jaci.2012.02.033
• 发表时间: 2012-05
• 期刊: The Journal of allergy and clinical immunology
• 作者: Sumino K;Tucker J;Shahab M;Jaffee KF;Visness CM;Gern JE;Bloomberg GR;Holtzman MJ
• 通讯作者: Holtzman MJ

Analysis of the contribution of MTP and the predicted Flp pilus genes to Mycobacterium tuberculosis pathogenesis.

• DOI: 10.1099/mic.0.000368
• 发表时间: 2016-10
• 期刊: Microbiology
• 影响因子: 1.5
• 作者: Katherine M Mann;A. C. Pride;Kelly N. Flentie;Jacqueline M. Kimmey;Leslie A. Weiss;Christina L. Stallings