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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.

摘要先天淋巴细胞是宿主抵抗病原体免疫的关键早期哨兵。研究最多的人先天淋巴细胞是自然杀伤(NK)细胞，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易感性，NK细胞缺乏会导致严重的健康并发症。此外对于NK细胞，一类天然淋巴样细胞(ILC)最近被证明在防止肠道、肺和皮肤等屏障表面的病原体感染。我们的长期计划目的是了解这些先天发育的分子机制。淋巴细胞，这将增加我们对这些细胞在感染期间的功能的了解。为此，我们最近发现了转录因子Nfil3(也称为E4BP4)在发育中的一个新角色 NK细胞和ILC家族的所有成员。使用老鼠病原体准确地模拟人类感染疾病，以及新产生的去除Nfil3基因或进化保守的调节域，这一R01拨款建议调查Nfil3是如何控制自然杀伤细胞和白细胞介素性细胞的发育及其抗病原体功能。在目标1中，我们将调查Nfil3是如何染色质免疫沉淀(CHIP)对先天淋巴细胞祖细胞转录调控的研究转录因子STAT5、PU.1、TCF-1和Ets-1，然后进行qPCR或深度测序(Seq)。在目标2中，我们将使用两个新的小鼠品系，其中包含CRISPR/Cas9靶向删除保守的非编码序列(称为Nfil3、CNS1和CNS2)，以确定内含子调节区对先天性的影响淋巴细胞的发育和抗病毒、蠕虫和细菌感染的效应器功能。在《目标3》中，我们将使用芯片序列、rna-seq和质谱仪来确定nfil3控制和结合的基因。影响Nfil3介导的对这些靶基因的调控的伙伴。总之，这项提案中的研究不仅增加了我们对NK细胞和ILC的一般分子机制的了解在病原体入侵期间发展和促进宿主防御，但也建立新的临床范例关于如何利用先天淋巴细胞室来治疗感染性疾病疾病。

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.