Transcriptional control in innate lymphoid type II cells

先天淋巴细胞 II 型细胞的转录控制

• 批准号: 8853814
• 负责人: Dorina Avram
• 金额: $ 18.6万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8853814
• 关键词: Acute; Adoptive Transfer; Amphiregulin; Applications Grants; Asthma; Behavior; Biology; Bone Marrow; Bystander Effect; Cell physiology; Cells; Chimera organism; Data; Development; Disease; Down-Regulation; Effectiveness; Epidermal Growth Factor; Epithelial; Excision; Exhibits; Future; Gene Expression; Generations; Genetic Programming; Health; Homeostasis; Hypersensitivity; Immune; Immune response; Immune system; Immunocompetent; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Influenza; Interleukin-13; Interleukin-17; Interleukin-5; Internal Ribosome Entry Site; Lung; Lung Inflammation; Lymphoid; Lymphoid Cell; Maintenance; Mediating; Mesentery; Neutrophil Infiltration; Papain; Pathology; Patient risk; Patients; Peripheral; Play; Population; Production; Pulmonary Inflammation; Rag1 Mouse; Role; Structure of parenchyma of lung; System; T-Lymphocyte; Testing; Therapeutic; Tissues; Transcription factor genes; Transcriptional Regulation; Type II Epithelial Receptor Cell; Up-Regulation; Virus Diseases; airway inflammation; airway remodeling; cell type; cytokine; eosinophil; in vivo; interleukin-22; lymph nodes; mouse model; programs; public health relevance; research study; response; therapeutic target; therapy development; tissue repair; transcription factor

DESCRIPTION (provided by applicant): Recent evidence shows that innate lymphoid type 2 cells (ILC2s) through production of IL-13 and IL-5 are critical in airway pathologies and tissue damage, strongly correlated with severe asthma. ILC2s not only produce IL-5 and IL-13, but also the epidermal growth factor amphiregulin, which promotes tissue remodeling and lung homeostasis following influenza infection. For developing therapeutic strategies to specifically target ILC2-mediated inflammation, while maintaining tissue repair activity, it is of crucial importance to delineate regulatory mechanisms involved in ILC2 development, maintenance and function. Our preliminary data demonstrate that Bcl11b is highly expressed in ILC2 cells in the periphery, as well as in bone marrow precursors. Induced removal of Bcl11b causes loss of their identity. Bcl11b-/- ILC2 population showed reduced IL-5 production following papain-induced lung inflammation, resulting in diminished eosinophil and increased neutrophil recruitment to the lung. Additionally, numbers of ILC2s were overall reduced in the bone marrow. In this grant application we propose to establish the role of Bcl11b in ILC2s lineage determination, in mature ILC2 cell function and identity and determine the mechanisms by which Bcl11b controls ILC2 genetic program.

描述(由申请人提供)：最近的证据表明，通过产生IL-13和IL-5而产生的先天淋巴样细胞2(ILC2s)在呼吸道病理和组织损伤中起关键作用，与严重哮喘密切相关。ILC2不仅产生IL-5和IL-13，而且还产生表皮生长因子双调节素，促进流感感染后的组织重塑和肺内稳态。为了开发针对ILC2介导的炎症的治疗策略，同时保持组织修复活性，描述ILC2的发生、维持和功能的调节机制是至关重要的。我们的初步数据表明，Bcl11b在外周ILC2细胞和骨髓前体细胞中高表达。诱导Bcl11b的移除会导致它们的身份丧失。在木瓜酶诱导的肺部炎症后，Bcl11b-/-ILC2群体显示IL-5的产生减少，导致嗜酸性粒细胞减少，中性粒细胞向肺内募集增加。此外，骨髓中ILC2的数量总体上减少了。在这项资助申请中，我们建议确定Bcl11b在ILC2s谱系确定中的作用，在成熟的ILC2细胞功能和识别中的作用，并确定Bcl11b控制ILC2遗传程序的机制。