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：
8612741
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/8612741
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 Commit Communicable Diseases Comparative Study Confusion Defect Dendritic Cells Developing Countries Development Disease Enteral Epithelial Cells Fetal Liver Genetic Genetic Models Hematopoietic Host Defense Hypersensitivity Immune Immune response Immune system Immunocompetent Immunodeficient Mouse In Vitro Infection Internal Ribosome Entry Site 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 cytokine human disease in vivo inhibitor/antagonist innovation insight mouse model novel novel strategies pathogen prevent progenitor public health relevance response tissue repair tool transcription factor

项目摘要

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 specific 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.

先天淋巴细胞（ILC）是存在于粘膜屏障并发挥关键的淋巴细胞的新型淋巴细胞种群在清除感染，诱导过敏性炎症或指导组织修复方面起作用。不同的谱系 ILC专门用于分泌极化的细胞因子，它们编排快速保护反应针对各种病原体。因此，他们的研究与各种各样的疾病有关西方和第三世界国家。 ILC的不同人群（包括ILC2S，ILC22S）之间的发展和谱系关系淋巴组织诱导剂（LTI）和NK细胞知之甚少，并且存在相当大的混乱关于这些ILC在健康状态和疾病背景下的身份和功能。在在体内对这些谱系的特异性操纵的缺乏，研究在很大程度上是仅限于缺乏适应性免疫系统的免疫缺陷小鼠，目前尚不清楚其结论是否得出将适用于普通动物。该项目以我们实验室生产的PLZF-IRES-GFPCRE记者小鼠的初步研究为基础表明转录因子PLZF先前被确定为先天性NKT细胞的特征在ILC2S和ILC22S的发展期间，谱系也以高水平表达，而不是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的发展和功能至关重要。该应用程序的目的是使用PLZF-IRES-GFPCRE 小鼠识别ILC的骨髓前体，表征其分子特征和遗传学在体内操纵ILC，以定义其在肠道感染良好模型中的功能。这具体目的是1）确定ILC谱系表达PLZF的骨髓前体的表征它的分子特征； 3）创建ILC缺陷的小鼠模型来研究肠道感染。提案具有创新性和意义 ILC的因素，并且因为它将在感染中生成研究模型免疫能力动物。