Regulation of innate lymphoid cells in inflammation

炎症中先天淋巴细胞的调节

基本信息

批准号：
9221244
负责人：
YUN-CAI LIU
金额：
$ 44.25万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-15 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9221244
关键词：
Affect Allergens Allergic Allergic Disease Allergic inflammation Biological Bone Marrow CD4 Positive T Lymphocytes Candidate Disease Gene Cell Count Cell Culture System Cell Differentiation process Cell Line Cell Maturation Cell physiology Cells Chimera organism Data Development Disease Enterobacteria phage P1 Cre recombinase Family GATA3 gene Gene Deletion Genes Genetic Glycolysis Goals HIF1A gene Hematopoiesis Human IL2 gene Immune Immune response In Vitro Infection Inflammation Inflammatory Interleukin-13 Interleukin-5 Interleukins Intestines Knock-out Knowledge Libraries Ligands Ligase LoxP-flanked allele Lung Lung Inflammation Lymphoid Cell Messenger RNA Metabolism Molecular Mus Papain Parasites Pathway interactions Peripheral Play Population Post-Translational Protein Processing Process Rag1 Mouse Regulation Research Rest Retroviridae Role Solid Stromal Cells System T-Cell Activation TSLP gene Testing Th1 Cells Tissues Transcriptional Regulation Tumor Suppressor Proteins Ubiquitin Ubiquitination Virus Diseases Work ZNF145 gene airway inflammation airway remodeling base cell type cytokine design experimental study immunoregulation in vivo knock-down member method development mouse model novel novel therapeutic intervention public health relevance repaired screening small hairpin RNA therapeutic development tissue repair transcription factor ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Group 2 innate lymphoid cells (ILC2s) are recently characterized as a new subset of lymphoid cell populations, which play pivotal roles in inducing allergic inflammation, clearing infections, and repairing damaged tissues. They secrete type 2 cytokines including interleukins 5 and 13 and are controlled by transcription factors Gata3 and Rorα. These cells are present in both mouse and humans and are involved in various disease developments. However, the underlying cellular and molecular mechanisms of regulation remain largely unknown. Our long-term goal is to study the process of protein modification by the ubiquitin tagging in immune responses. We thus performed preliminary studies to explore the roles of E3 ubiquitin ligases in ILC2s by using conditional deletions of genes in mouse models, and found that the deficiency of VHL E3 ligase component results in defective development of ILC2s in the lungs, whereas loss of Fbw7, another E3 ligase component, caused defective differentiation in the bone marrow under steady state, and reduced lung ILC2 numbers upon allergen exposure. These preliminary studies indicate that the ubiquitin system is important for ILC2s, and allow us to hypothesize that they function at different stages of ILC2 differentiation via targeting the ubiquitination of their targets. To test this central hypothesis,we propose the following two major aims: Specific Aim 1: To study VHL in ILC2 maturation and function in the lungs. Specific Aim 2: To study Fbw7 in ILC2 development in the bone marrow and function in the lungs. We will use a combination of in vitro and in vivo feasible approaches, with complementary alternatives. The expected results will significantly move this field forward, and will have impact on the development of therapeutic methods and/or targets for inflammatory diseases and infection.

描述（由申请人提供）：第 2 类先天淋巴样细胞 (ILC2) 最近被定性为淋巴样细胞群的新亚群，其在诱导过敏性炎症、清除感染和修复受损组织中发挥关键作用，它们分泌包括 2 型细胞因子的细胞因子。白细胞介素 5 和 13 受转录因子 Gata3 和 Rorα 控制，这些细胞存在于小鼠和人类中，并参与多种疾病的发展。我们的长期目标是研究免疫反应中泛素标记的蛋白质修饰过程，因此我们通过在小鼠模型中条件性基因删除来探索 E3 泛素连接酶在 ILC2 中的作用。，并发现 VHL E3 连接酶成分的缺乏导致肺部 ILC2 的发育缺陷，而另一种 E3 连接酶成分 Fbw7 的缺失导致肺中 ILC2 的分化缺陷。这些初步研究表明，泛素系统对于 ILC2 很重要，并且使我们能够认为它们通过靶向其靶标的泛素化而在 ILC2 分化的不同阶段发挥作用。为了检验这一中心假设，我们提出以下两个主要目标：具体目标 1：研究 VHL 在 ILC2 成熟和肺部功能中的作用。 ILC2 在骨髓中的发育和在肺部的功能我们将结合使用体外和体内可行的方法以及互补的替代方案，预期结果将显着推动该领域的发展，并对治疗方法的开发产生影响。和/或炎症性疾病和感染的靶标。