A common hematopoietic precursor to innate lymphoid cells

先天淋巴细胞的常见造血前体

基本信息

批准号：
9110098
负责人：
ALBERT S. BENDELAC
金额：
$ 38.39万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9110098
关键词：
Adult Allergic Disease Allergic inflammation Animals Automobile Driving Bacterial Infections Bone Marrow Candidate Disease Gene Categories Cell Lineage Cells Citrobacter rodentium Classification Communicable Diseases Comparative Study Confusion Defect Dendritic Cells Developing Countries Development Disease Enteral Epithelial Cells Fetal Liver Genetic Genetic Models Health Hematopoietic Host Defense Hypersensitivity Immune Immune system Immunocompetent Immunodeficient Mouse In Vitro Infection Internal Ribosome Entry Site Knockout Mice Knowledge Laboratories Lymphocyte Lymphocyte Subset Lymphoid Lymphoid Cell Lymphoid Tissue Maps Mission Modeling Molecular Molecular Profiling Mus Myelogenous Natural Killer Cells Nippostrongylus Organ Culture Techniques Parasitic infection Physiology Play Population Public Health Reporter Research Role Staging Study models System Testing United States National Institutes of Health Virus Diseases Work ZNF145 gene adaptive immunity cytokine genetic approach human disease in vivo inhibitor/antagonist innovation insight microbiota mouse model novel novel strategies pathogen prevent progenitor response tissue repair tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): Innate lymphocytes (ILC) are novel populations of lymphocytes that reside at mucosal barriers and play critical functions in clearing infections, inducing allergic inflammation or directing tissue repair. Different lineages of ILCs are specialized in the secretion of polarized sets of cytokines that orchestrate rapid protective responses against various categories of pathogens. Thus, their study is relevant to a broad range of diseases across western and third-world countries. The development and the lineage relationships between different populations of ILCs, including ILC2s, ILC22s, lymphoid tissue inducers (LTis) and NK cells, are poorly understood and there is considerable confusion regarding the identity and function of these ILCs in the healthy state and in the context of disease. In the absence of genetic models alowing specific manipulation of these lineages in vivo, studies have been largely limited to immunodeficient mice lacking an adaptive immune system and it is unclear whether their conclusions will apply to normal animals. This project builds on preliminary studies of PLZF-IRES-GFPCre reporter mice produced in our laboratory showing that the transcription factor PLZF, previously identified as the signature of the innate-like NKT cell lineage, is also expressed at high levels during the development of ILC2s and ILC22s but not NK or LTi cells. The central hypothesis is that PLZF marks a common bone marrow precursor to ILC2s and ILC22s and is essential for normal development and function. The objective of this application is to use PLZF-IRES-GFPCre mice to identify the bone marrow precursors of ILCs, characterize their molecular signature and genetically manipulate ILCs in vivo in order to define their function in well-established models of enteric infections. The specifc aims are 1) to identify the PLZF-expressing bone marrow precursor of ILC lineages, 2) to characterize its molecular signature; 3) to create ILC-defective mouse models for studies of enteric infections. The proposal is innovative and significant because it identifies a novel bone marrow precursor and a novel transcription factor for ILCs and because it will produce models for studies of ILCs in the context of infections in immunocompetent animals.

描述（由申请人提供）：先天淋巴细胞（ILC）是存在于粘膜屏障的新型淋巴细胞种群，并在清除感染，引起过敏性炎症或指导组织修复方面起着关键功能。 ILC的不同谱系专门用于分泌一组极化的细胞因子，这些细胞因子策划了针对各种病原体的快速保护反应。因此，他们的研究与西方和第三世界国家的各种疾病有关。知识渊博，包括ILC2，ILC22S，淋巴组织诱导剂（LTI）和NK细胞在内的不同种群的ILC种群之间的发展和谱系关系知之甚少，并且在健康状态和疾病的背景下，这些ILC的身份和功能都存在很大的混淆。在没有遗传模型的情况下，在体内对这些谱系的特异性操纵的情况下，研究在很大程度上仅限于缺乏适应性免疫系统的免疫缺陷小鼠，目前尚不清楚它们的结论是否适用于正常动物。该项目的基于我们实验室中产生的PLZF-IRES-GFPCRE记者小鼠的初步研究，表明，以前被确定为先天天生的NKT细胞谱系的转录因子PLZF在ILC2S和ILC22S和ILC22S的开发过程中也以高水平表达，但不是NK或NK或LTI细胞。中心假设是PLZF标志着ILC2S和ILC22S的常见骨髓前体，对于正常发育和功能至关重要。该应用的目的是使用PLZF-IRES-GFPCRE小鼠鉴定ILC的骨髓前体，以体内表征其分子特征，并在体内遗传操纵ILC，以定义其在熟悉的肠道感染模型中的功能。指定的目的是1）识别ILC谱系表达PLZF的骨髓前体，2）表征其分子特征； 3）创建ILC缺陷的小鼠模型来研究肠道感染。该提案具有创新性和意义，因为它可以识别出新型的骨髓前体和ILC的新型转录因子，并且因为它将在免疫能力动物的感染中生成用于研究ILC的模型。