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
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Mengfei Liu其他文献
Mengfei Liu的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
相似海外基金
Biomarkers of Disease in Alcoholic Hepatitis Administrative Supplement
酒精性肝炎行政补充剂中疾病的生物标志物
- 批准号:
10840220 - 财政年份:2023
- 资助金额:
$ 19.06万 - 项目类别:
Evaluation of oral administration of PRIM-DJ2727 capsule containing microbiota suspension in patients with severe alcoholic hepatitis: An Open-Label Study
严重酒精性肝炎患者口服含有微生物悬浮液的 PRIM-DJ2727 胶囊的评价:一项开放标签研究
- 批准号:
10527603 - 财政年份:2022
- 资助金额:
$ 19.06万 - 项目类别:
Evaluation of oral administration of PRIM-DJ2727 capsule containing microbiota suspension in patients with severe alcoholic hepatitis: An Open-Label Study
严重酒精性肝炎患者口服含有微生物悬浮液的 PRIM-DJ2727 胶囊的评价:一项开放标签研究
- 批准号:
10686094 - 财政年份:2022
- 资助金额:
$ 19.06万 - 项目类别:
An innovative non-thiazolidinedione pan-PPAR agonist therapeutic for Alcoholic Hepatitis
一种创新的非噻唑烷二酮类泛 PPAR 激动剂,用于治疗酒精性肝炎
- 批准号:
10482468 - 财政年份:2022
- 资助金额:
$ 19.06万 - 项目类别:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
酒精性肝炎中中性粒细胞和胆管细胞之间的相互作用
- 批准号:
10298412 - 财政年份:2021
- 资助金额:
$ 19.06万 - 项目类别:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
酒精性肝炎中中性粒细胞和胆管细胞之间的相互作用
- 批准号:
10494268 - 财政年份:2021
- 资助金额:
$ 19.06万 - 项目类别:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
酒精性肝炎中中性粒细胞和胆管细胞之间的相互作用
- 批准号:
10617893 - 财政年份:2021
- 资助金额:
$ 19.06万 - 项目类别:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
酒精性肝炎中中性粒细胞和胆管细胞之间的相互作用
- 批准号:
10646369 - 财政年份:2021
- 资助金额:
$ 19.06万 - 项目类别:
Interactions between neutrophils and cholangiocytes in alcoholic hepatitis
酒精性肝炎中中性粒细胞和胆管细胞之间的相互作用
- 批准号:
10874892 - 财政年份:2021
- 资助金额:
$ 19.06万 - 项目类别: