IL17 dependent angiocrine signaling drives inflammation in alcohol associated hepatitis
IL17 依赖性血管分泌信号传导驱动酒精相关性肝炎的炎症
基本信息
- 批准号:10837927
- 负责人:
- 金额:$ 19.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-09-01 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAlcoholic HepatitisAlcoholic Liver DiseasesAutoimmuneBiologicalBiological AssayBlood VesselsCXCL1 geneCellsChemotaxisChromatin Conformation Capture and SequencingCirculationClinicalClustered Regularly Interspaced Short Palindromic RepeatsComplexDNADataDevelopmentDiscontinuous CapillaryDiseaseDominant-Negative MutationEndothelial CellsEndotheliumEnhancersFamilyGene ExpressionGenesGenomeGuide RNAHeavy DrinkingHereditary DiseaseIL17 geneImmuneInfiltrationInflammationInflammatoryInflammatory ResponseInterleukin SuppressionKnock-inKnock-in MouseKnockout MiceKnowledgeLigandsLiverLiver parenchymaMediatingMicrofluidic MicrochipsMissionModelingMolecular TargetMusNational Institute on Alcohol Abuse and AlcoholismNeutrophil InfiltrationNuclearParacrine CommunicationPathogenesisPathway AnalysisPathway interactionsPatientsPhosphorylationProcessProductionProtein IsoformsRegulationRegulator GenesRegulatory ElementRoleSignal PathwaySignal TransductionSmall Interfering RNASourceSystemT-LymphocyteT-Lymphocyte SubsetsTNF geneTestingThreonineTissuesTranscriptional RegulationTransgenic MiceUp-RegulationVariantViralWorkalcohol abuse therapychemokinechromatin immunoprecipitationchromosome conformation capturecytokineexperimental studygene networkimmune activationimmune cell infiltratein vivoinhibitorliver inflammationliver injurymembermigrationmouse modelneutrophilnew therapeutic targetnovelnovel therapeuticsparacrinepharmacologicpromoterresponsesynergismtargeted treatmenttherapeutic targettranscription factortranscriptome sequencingtranscriptomics
项目摘要
Project Abstract
Alcoholic hepatitis (AH) is characterized by intense liver inflammation and injury in the setting of excess alcohol
ingestion. Cytokine and chemokine upregulation leads to immune cell infiltration and drives inflammation in AH.
Liver sinusoidal endothelial cells (LSEC) are an important source of chemokine expression in the liver and
participate in paracrine signaling to attract immune cells in a process termed “angiocrine signaling”. Pathway
analysis of AH liver RNA-sequencing suggests a potential role of IL17 in mediating LSEC angiocrine signaling.
IL17 is a cytokine involved in many autoimmune and inflammatory disorders. Our preliminary data shows that
IL17 synergically stimulate CXCL chemokine production with TNF, but the underlying mechanism is not clear.
The regulation of IL17 production from T cells also requires further study. Super enhancers are DNA regulatory
elements that complex with target gene promoters to drive gene expression. Our previous work has highlighted
the role of super enhancers in AH inflammation response. Here, we hypothesize that LSECs increase
inflammatory chemokine expression and enhance immune cell transmigration into the liver parenchyma
in response to T cell IL17 upregulation by super enhancer activation. To test our hypothesis, we will employ
complementary cell biologic and in vivo approaches to study the following specific aims: Aim 1. LSECs enhance
CXCL1-dependent neutrophil transendothelial migration in response to IL17; Aim 2. Therapeutic
targeting of a super enhancer in T cells downregulates IL17 and ameliorates inflammation in AH. In Aim
1, we will explore the role of IκB𝜁, a transcription factor previously implicated in IL17 signaling, in mediating the
interaction between IL17 and TNF signaling pathways. We will also assess the transcriptomic changes of IL17
and TNF stimulation and IκB𝜁 silencing on LSECs by RNA-sequencing. Using microfluidic devices to simulate
liver microvascular circulation, we will directly observe the effects of IL17/TNF stimulation and IκB𝜁 inhibition
on neutrophil chemotaxis. In Aim 2, we will identify the IL17 super enhancer by chromosome conformation
capture assays. We will assess the feasibility of CRISPR-mediated sequence-specific suppression of the IL17
super enhancer. We will use a Cre dependent dCas9-KRAB knockin mice with AAV6 viral delivery of single guide
RNA to target the IL17 super enhancer in vivo. We aim to achieve T cell-specific suppression of IL17 expression
and assess its effect on AH inflammatory response in a murine model. Indeed, in vivo CRISPR gene-editing has
already been applied clinically to treat hereditary disorders, highlighting the translational promise of precision
genome-targeting therapies. Better understanding of the IL17 mediated angiocrine signaling process and IL17
super enhancer regulation may reveal novel therapeutic targets for treatment of AH. Therefore, our overall aims
and approaches are aligned with the mission of NIAAA to further understanding and treatment of alcohol-
associated liver diseases.
项目摘要
酒精性肝炎(AH)的特点是严重的肝脏炎症和损伤的设置过量酒精
摄入细胞因子和趋化因子上调导致免疫细胞浸润并驱动AH中的炎症。
肝窦内皮细胞(LSEC)是肝脏中趋化因子表达的重要来源,
参与旁分泌信号传导以在称为“血管分泌信号传导”的过程中吸引免疫细胞。途径
AH肝RNA测序的分析表明IL 17在介导LSEC血管分泌信号传导中的潜在作用。
IL 17是参与许多自身免疫性和炎性病症的细胞因子。我们的初步数据显示,
IL 17与TNF α协同刺激CXCL趋化因子的产生,但其潜在机制尚不清楚。
从T细胞产生IL 17的调节也需要进一步研究。超级增强子是DNA调控
与靶基因启动子复合以驱动基因表达的元件。我们之前的工作
超级增强子在AH炎症反应中的作用。在这里,我们假设LSEC增加
炎性趋化因子表达和增强免疫细胞向肝实质的迁移
响应于通过超级增强子激活的T细胞IL 17上调。为了验证我们的假设,我们将使用
补充细胞生物学和体内方法来研究以下具体目标:目的1. LSEC增强
CXCL 1依赖性中性粒细胞跨内皮迁移响应IL 17;目的2.治疗
靶向T细胞中的超级增强子下调IL 17并改善AH中的炎症。在Aim中
1,我们将探讨IκBβ,一种先前参与IL 17信号转导的转录因子,在介导IL 17信号转导中的作用。
IL 17和TNF α信号通路之间的相互作用。我们还将评估IL 17的转录组学变化,
和TNF β刺激和IκBβ沉默。利用微流体装置模拟
直接观察IL 17/TNF β刺激和IκB抑制对肝脏微血管循环的影响
对中性粒细胞趋化性的影响在目标2中,我们将通过染色体构象鉴定IL 17超级增强子
捕获测定。我们将评估CRISPR介导的IL 17序列特异性抑制的可行性。
超级增强剂我们将使用Cre依赖性dCas 9-KRAB敲入小鼠,其中AAV 6病毒递送单向导RNA。
RNA在体内靶向IL 17超级增强子。我们的目标是实现T细胞特异性抑制IL 17表达
并评估其对小鼠模型中AH炎症反应的作用。事实上,体内CRISPR基因编辑
已经在临床上应用于治疗遗传性疾病,突出了精确的转化承诺
基因组靶向治疗更好地理解IL 17介导的血管分泌信号传导过程和IL 17
超级增强子调控可能揭示治疗AH的新的治疗靶点。因此,我们的总体目标
和方法与NIAAA的使命一致,以进一步了解和治疗酒精-
相关的肝脏疾病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Mengfei Liu', 18)}}的其他基金
IL17 dependent angiocrine signaling drives inflammation in alcohol associated hepatitis
IL17 依赖性血管分泌信号传导驱动酒精相关性肝炎的炎症
- 批准号:
10570615 - 财政年份:2022
- 资助金额:
$ 19.06万 - 项目类别:
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