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) 是一种新的淋巴细胞群，驻留在粘膜屏障中并发挥着关键作用具有清除感染、诱发过敏性炎症或指导组织修复的功能。不同的血统 ILC 专门分泌极化细胞因子组，协调快速保护反应对抗各种类别的病原体。因此，他们的研究与多种疾病相关西方和第三世界国家。 ILCs不同群体的发育和谱系关系，包括ILC2s、ILC22s、人们对淋巴组织诱导剂 (LTis) 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。在由于缺乏允许在体内对这些谱系进行特定操作的遗传模型，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，尚不清楚他们的结论是否有效将适用于正常动物。该项目建立在我们实验室生产的 PLZF-IRES-GFPCre 报告小鼠的初步研究基础上显示转录因子 PLZF，之前被鉴定为先天性 NKT 细胞的特征谱系，在 ILC2 和 ILC22 的发育过程中也高水平表达，但在 NK 或 LTi 细胞中不表达。中心假设是 PLZF 标志着 ILC2 和 ILC22 的共同骨髓前体，并且是对于正常发育和功能至关重要。此应用程序的目标是使用 PLZF-IRES-GFPCre 小鼠鉴定 ILC 的骨髓前体，表征其分子特征并进行遗传分析在体内操纵 ILC，以确定其在完善的肠道感染模型中的功能。这具体目标是 1) 鉴定表达 PLZF 的 ILC 谱系骨髓前体，2) 表征它的分子特征； 3) 创建ILC缺陷小鼠模型用于肠道感染研究。提案具有创新性和意义，因为它鉴定了一种新的骨髓前体和一种新的转录 ILC 的因素，因为它将产生在感染背景下研究 ILC 的模型免疫能力强的动物。