Regulation of Nfil3 in innate lymphocyte-mediated host immunity

Nfil3 在先天淋巴细胞介导的宿主免疫中的调节

基本信息

批准号：
10112809
负责人：
Joseph Chai-Yuen Sun
金额：
$ 56.76万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112809
关键词：
Antigens B-Lymphocytes Bacterial Infections Binding Binding Sites Biological Assay Blood Circulation CRISPR/Cas technology Cell Compartmentation Cell Line Cell physiology Cells ChIP-seq Characteristics Citrobacter rodentium Clinical Clostridium difficile Common Lymphoid Progenitor Communicable Diseases Data Defect Development E4BP4 Education Enhancers Epithelial Exhibits Family Gene Targeting Generations Genes Genetic Transcription Goals Grant Growth Health Herpesviridae Infections Host Defense Human IL7 gene Immunity Infection Interleukin 2 Receptor Gamma Interleukin-15 Interleukin-2 Intestines Introns Invaded Luciferases Lung Lymphocyte Lymphoid Cell Mammals Mass Spectrum Analysis Mediating Memory Molecular Mouse Strains Mucous Membrane Murid herpesvirus 1 Mus Names Natural Killer Cells Nippostrongylus Nucleic Acid Regulatory Sequences Organ Play Predisposition Process Proteomics Regulation Research Research Project Grants Role Sentinel Signal Transduction Skin Stat5 protein Surface T-Lymphocyte Testing Therapeutic Tissues Transcriptional Regulation Transgenic Mice Untranslated RNA Viral Virus Virus Diseases Work chromatin immunoprecipitation cytokine deep sequencing differential expression fighting gastrointestinal genome editing helminth infection human model influenzavirus member mouse model novel pathogen progenitor promoter protein complex public health relevance response stem cells transcription factor transcriptome sequencing

项目摘要

ABSTRACT Innate lymphocytes represent early sentinels critical in host immunity against pathogens. The best studied innate lymphocyte is the natural killer (NK) cell, which specifically targets virally-infected host cells. Humans deficient in NK cells have severe health complications due to susceptibility to herpesvirus infections. In addition to NK cells, a family of innate lymphoid cells (ILC) has recently been demonstrated to play an important role in protection against pathogen infection at barrier surfaces such as the intestine, lung, and skin. Our long term goals are to understand the the molecular mechanisms underlying the development of these innate lymphocytes, which will increase our understanding of the function of these cells during infection. To this end, we have recently identified a novel role for the transcription factor Nfil3 (also known as E4BP4) in development of NK cells and all members of the ILC family. Using mouse pathogens that accurately model human infectious diseases, along with newly-generated transgenic mouse models that ablate either the Nfil3 gene or evolutionarily-conserved regulatory domains, this R01 grant proposes to investigate how Nfil3 is controling the development and anti-pathogen functions of NK cells and ILCs. In Aim 1, we will investigate how Nfil3 is transcriptionally regulated in innate lymphocyte progenitors by chromatin immunoprecipitation (ChIP) for the transcription factors STAT5, PU.1, TCF-1, and Ets-1 followed by qPCR or deep sequencing (seq). In Aim 2, we will use two novel mouse strains containing a CRISPR/Cas9-targeted deletion of conserved noncoding sequences (termed Nfil3 CNS1 and CNS2) to determine the influence of intronic regulatory regions on innate lymphocyte development and effector function against virus, helminth, and bacterial infection. In Aim 3, we will use ChIP-seq, RNA-seq, and mass spectrometry to determine the genes that Nfil3 is controlling, and binding partners that influence Nfil3-mediated regulation of these target genes. Together, the studies in this proposal will not only increase our understanding of the general molecular mechanisms whereby NK cells and ILCs develop and contribute to host defense during pathogen invasion, but also establish novel clinical paradigms for how the innate lymphocyte compartment may be harnessed for therapeutic strategies against infectious disease.

抽象的先天淋巴细胞代表了宿主免疫对病原体至关重要的早期哨兵。最好的研究先天淋巴细胞是天然杀手（NK）细胞，它专门针对病毒感染的宿主细胞。人类由于对疱疹病毒感染的敏感性，NK细胞缺乏患有严重的健康并发症。此外对于NK细胞，最近已证明了一个先天淋巴样细胞（ILC）家族在防止病原体感染在障碍物表面，例如肠，肺和皮肤。我们的长期目标是了解这些先天性发展的分子机制淋巴细胞将增加我们对感染过程中这些细胞功能的理解。为此，我们最近确定了转录因子NFIL3（也称为E4BP4）的新作用 NK细胞和ILC家族的所有成员。使用精确模拟人类感染的小鼠病原体疾病，以及新生成的转基因小鼠模型，可以消灭NFIL3基因或该R01赠款提出了进化保存的调节域，提议研究NFIL3如何控制 NK细胞和ILC的发育和抗病原体功能。在AIM 1中，我们将调查NFIL3是如何通过染色质免疫沉淀（CHIP）在先天淋巴细胞祖细胞中进行转录调节转录因子STAT5，PU.1，TCF-1和ETS-1，然后进行QPCR或深层测序（SEQ）。在AIM 2中，我们将使用两个新型的鼠标菌株，其中包含CRISPR/CAS9为符合保守的非编码的删除序列（称为NFIL3 CNS1和CNS2）确定内含子调节区域对先天性的影响淋巴细胞发育和效应子功能针对病毒，蠕虫和细菌感染。在AIM 3中，我们将使用chip-seq，RNA-seq和质谱法确定NFIL3正在控制的基因和结合影响NFIL3介导的这些靶基因调节的伴侣。共同的研究中的研究不仅会增加我们对NK细胞和ILC的一般分子机制的理解在病原体入侵期间发展并促进宿主防御，但也建立了新的临床范例关于如何利用先天淋巴细胞室的治疗策略疾病。

项目成果

期刊论文数量（30）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Epigenetic regulation of natural killer cell memory.

DOI：
10.1111/imr.13031
发表时间：
2022-01
期刊：
Immunological reviews
影响因子：
8.7
作者：
Lau CM;Wiedemann GM;Sun JC
通讯作者：
Sun JC

ILC1 Confer Early Host Protection at Initial Sites of Viral Infection.

DOI：
10.1016/j.cell.2017.09.052
发表时间：
2017-11-02
期刊：
Cell
影响因子：
64.5
作者：
Weizman OE;Adams NM;Schuster IS;Krishna C;Pritykin Y;Lau C;Degli-Esposti MA;Leslie CS;Sun JC;O'Sullivan TE
通讯作者：
O'Sullivan TE

Epigenetic control of innate and adaptive immune memory.