Functional role of the transcription factor NFATc1 in allergic asthma

转录因子 NFATc1 在过敏性哮喘中的功能作用

• 批准号: 317670839
• 负责人: Professorin Dr. Susetta Finotto, Ph.D.
• 金额: --
• 依托单位: Abteilung Molekulare Pneumologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/317670839?language=en
• 关键词: Functional; role; transcription; factor; NFATc1

Allergic asthma is a chronic inflammatory disease of the airways that affects millions of people world-wide. NFATc1, a member of the nuclear factor of activated T cells (NFAT) transcription factor family, is regulated in cells controlling both innate and adaptive immune responses and contributes to their effector function and cell homeostasis. In previous studies, we analyzed the role of NFATc1 in T cells in a murine model of allergic asthma by using NFATc1fl/fl control mice and NFATc1fl/flxCD4Cre mice after OVA sensitization and challenge. In the last funding period, we extended this observation to a second model of asthma with higher relevance for human allergic asthma induced by House dust mite (HDM) sensitization and challenge and demonstrated that NFATc1 deficiency in T cells results in impaired differentiation of Th2 cells and induction of airway tolerance in allergic asthma. Moreover, in the HDM model of asthma, targeting NFATc1 in CD19+ B cells in the newly generated NFATc1fl/flxCD19Cre resulted in reduced airway hyperresponsiveness and suppressed serum IgE levels. Furthermore, we recently investigated the role of NFAT-interacting protein (NIP)-45, an IL-4 inducing Transcription Factor in the pathogenesis of asthma. NIP45 mRNA was found to be induced in blood cells of asthmatic pre-school children. Targeted deletion of NIP45 in mice resulted in a protective phenotype in models of asthma associated with reduced mucus production and impaired airway hyperresponsiveness. In addition to NFATc1 and NIP45, also NFATc2 was found to be up-regulated in peripheral blood mononuclear cells from asthmatic children and adults with allergic asthma. In conclusion, targeting NFATc in T and B lymphocytes might ameliorate the allergic phenotype in asthmatic subjects.In this grant application, we want to continue to identify the target genes of NFATc1 in murine lung CD4+ T as well as B cells by extending the analysis to the NFATc1-mb-1Cre mice in HDM induced asthma. Moreover, to further investigate the role of NFATc1 in airway tolerance as therapy for asthma, we want to delete NFATc1 in dendritic cells by creating the conditional gene targeting NFATc1fl/flCD11cCre+ mice. Finally, we will study the role of NFATc1 in sorted human DCs, T and B cells isolated from the peripheral blood of control and asthma adult patients in a new clinical study, denoted AZCRA. We then will perform RNA seq to profile gene expression in human DCs, T and B cells respectively. In summary, this project aims to shed light on the role of NFATc1 in T, B and DC cells in allergic asthma in order to design novel therapeutic approaches for this disease.

过敏性哮喘是一种慢性气道炎症性疾病，影响全球数百万人。NFATc 1是活化T细胞核因子（NFAT）转录因子家族的成员，在控制先天性和适应性免疫应答的细胞中受到调节，并有助于其效应子功能和细胞稳态。在以前的研究中，我们分析了NFATc 1在过敏性哮喘小鼠模型T细胞中的作用，使用NFATc 1fl/fl对照小鼠和NFATc 1fl/flxCD 4Cre小鼠在OVA致敏和激发后。在上一个资助期，我们将这一观察结果扩展到第二个哮喘模型，该模型与屋尘螨（HDM）致敏和激发诱导的人类过敏性哮喘具有更高的相关性，并证明T细胞中NFATc 1缺乏导致Th 2细胞分化受损和过敏性哮喘中气道耐受的诱导。此外，在HDM哮喘模型中，靶向新产生的NFATc 1 fl/flxCD 19 Cre中CD 19 + B细胞中的NFATc 1导致气道高反应性降低和血清IgE水平抑制。 此外，我们最近研究了NFAT相互作用蛋白（NIP）-45，一种IL-4诱导转录因子在哮喘发病机制中的作用。发现哮喘学龄前儿童血细胞中NIP 45 mRNA被诱导。在小鼠中靶向缺失NIP 45导致与粘液产生减少和气道高反应性受损相关的哮喘模型中的保护性表型。除了NFATc 1和NIP 45，还发现NFATc 2在哮喘儿童和过敏性哮喘成人的外周血单核细胞中上调。总之，靶向T和B淋巴细胞中的NFATc可能改善哮喘受试者的过敏表型。在本授权申请中，我们希望通过将分析扩展到HDM诱导的哮喘中的NFATc 1-mb-1Cre小鼠，继续鉴定小鼠肺CD 4 + T细胞和B细胞中的NFATc 1靶基因。此外，为了进一步研究NFATc 1在气道耐受中作为哮喘治疗的作用，我们希望通过创建靶向NFATc 1fl/flCD 11 cCre+小鼠的条件基因来删除树突状细胞中的NFATc 1。最后，我们将在一项新的临床研究中研究NFATc 1在从对照和哮喘成人患者外周血分离的分选的人DC、T和B细胞中的作用，该研究被称为AZCRA。然后我们将进行RNA测序以分别分析人DC、T和B细胞中的基因表达。总之，本项目旨在阐明NFATc 1在T、B和DC细胞中在过敏性哮喘中的作用，以设计针对这种疾病的新治疗方法。