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Mechanistically based therapeutic strategies in murine primary biliary cholangitis

Mechanistically based therapeutic strategies in murine primary biliary cholangitis
小鼠原发性胆汁性胆管炎的机制治疗策略
批准号:
10553286
负责人:
MERRILL E GERSHWIN
金额:
$38.99万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-02-10 至 2025-01-31
关键词:
3&apos Untranslated RegionsAcetatesAddressAmyloseAnimal ModelAntibodiesAutoantigensAutoimmuneAutoimmune DiseasesAutoimmune ProcessAutoimmunityB-LymphocytesBile AcidsBiologyButyratesCCR6 geneCXCR3 geneCell CompartmentationCellsCholangitisCoinCollaborationsColonComplementDataDefectDevelopmentDiabetes MellitusDietDiseaseElementsEndowmentEnzymesEpigenetic ProcessExcisionFemaleFibrosisFutureGenesGenetic Complementation TestGoalsHepatologyHistonesHumanImmuneImmune ToleranceImmunologyInbred NOD MiceIndividualInflammationInterferon ReceptorInterferon Type IInterferon Type IIInterleukin-12LinkLiverLiver diseasesMaizeMediatingModelingMolecular BiologyMonoclonal AntibodiesMusNatural HistoryPaperPathogenicityPathologyPathway AnalysisPathway interactionsPersonsPilot ProjectsPlayPortal vein structurePreventionPrimary biliary cirrhosisPruritusPublishingReceptor SignalingRefractoryRegulationRegulatory T-LymphocyteResourcesRoleSeverity of illnessSex BiasSignal PathwaySignal TransductionStarchStructure of germinal center of lymph nodeTLR7 geneTherapeuticUnited States National Institutes of HealthVolatile Fatty AcidsWorkX ChromosomeX Inactivationalternative treatmentautoreactive B cellautoreactivitycomparative efficacydietaryeditorialexperiencegenome wide association studygut microbiomegut microbiotaimmunoregulationinhibitorinnovationmetabolomicsmolecular pathologymultidisciplinarynovel strategiesnovel therapeutic interventionpreventrestorationsmall moleculetreatment responsetreatment strategytype I interferon receptor

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中文摘要
翻译
摘要 原发性胆管炎(PBC)的治疗落后于其他自身免疫性疾病。我们建议 与我们在代谢组学、免疫学、分子生物学等方面拥有专业知识的多学科团队一起挑战这一空白 生物学和病理学。我们认为,我们对ARE-/-小鼠的使用是一个强大的新模型,因为小鼠概括地说 以女性为主的人PBC,AMAS,门脉炎症,总胆汁酸升高,瘙痒,纤维化 以及TLR7介导的功能所需的I型干扰素(干扰素)的女性表达增加。我们将首先 提出了一种治疗自身免疫的全新方法,在这种方法中,致病免疫细胞在 联合肠道微生物代谢物治疗可恢复耐受性。自身免疫性肝病是治疗 这样的疗法是因为肝脏位于结肠的上游。的确,如果去除了致病细胞,接下来 由于耐受性饮食在PBC中起作用(我们的目标1),它应该会导致其他自身免疫性疾病的试验。Th1或Th17 细胞去除是一种根本性的新方法,重要的是要用对个体的理解来补充这一点 Th1或Th17/Tfh/生发中心途径分子,以了解Th1或Th17是否为生物学基础 中国人民银行。我们将通过调节TLR7和改变来下调效应器功能,从而解决途径参与问题 生发中心功能(目标2)和/或直接寻址干扰素受体信号(目标3)。这些目标是 基于我们的数据,以及直接针对自身免疫性胆管炎机制的独特资源。我们的 该集团拥有丰富的已发表/未发表的数据,包括在调节自身免疫方面的丰富经验 通过饮食和代谢物。因此,我们的三个目标首先是通过抗体耗尽来消除致病细胞 Th1(CXCR3单抗)或Th17和Tfh(CCR6单抗),随后进行免疫恢复/调节 细菌的代谢物,可以提高耐受性和耐受性。这一步骤涉及使用火腿(高直链淀粉 玉米淀粉)能产生大量内脏丁酸盐或醋酸盐的饮食。这种方法已经奏效了 令人惊叹的是,我们手中的糖尿病在NOD小鼠身上表现良好。我们的第二个目标是调节TLR7,这对 在雌性Are-/-小鼠中形成GC,预防疾病;TLR7在雌性Are-/-小鼠中高表达。 这些数据可能会带来未来使用靶向TLR7信号的小分子的机会。在我们的第三个和 最终目的我们认为抑制I型干扰素受体信号将具有治疗作用。我们知道删除 ARE-/-小鼠体内的I型干扰素受体可降低疾病严重程度。因此,我们将用单抗阻断干扰素受体 和JAK/STAT信号与JAK抑制剂。总而言之,我们认为这项提议是创新的,很可能导致 更好的治疗方法,不仅在PBC中,而且在其他自身免疫中也具有重要意义 疾病。
英文摘要
Summary The treatment of primary biliary cholangitis (PBC) has lagged behind other autoimmune diseases. We propose to challenge this void with our multidisciplinary team with expertise in metabolomics, immunology, molecular biology and pathology. We submit that our use of ARE–/– mice are a powerful new model as mice recapitulate human PBC with female predominance, AMAs, portal inflammation, increased total bile acids, itching, fibrosis and elevated female expression of type I interferon (IFN), required for TLR7 mediated function. We will first propose an entirely new approach to treat autoimmunity, in which depletion of pathogenic immune cells in combination with gut microbiome metabolite therapy restores tolerance. Autoimmune liver diseases are ideal for such therapies because the liver is situated upstream from the colon. Indeed, if pathogenic cell removal, followed by tolerogenic diets work in PBC (our Aim 1), it should lead to trials in other autoimmune diseases. Th1 or Th17 cell removal is a radical new approach, and it is important to complement this with understanding of individual Th1 or Th17/Tfh/germinal centre pathway molecules, to understand whether Th1 or Th17 biology underpins PBC. We will address pathway involvement by downregulating effector function by modulating TLR7 and altering germinal center function (Aim 2) and/or directly addressing IFN receptor signaling (Aim 3). These goals are based on our data, and unique resources that directly target the mechanisms of autoimmune cholangitis. Our group has a wealth of published/unpublished data including extensive experience in modulating autoimmunity by diet and metabolites. Hence our three goals are firstly to eliminate pathogenic cells through antibody depletion of Th1 (CXCR3 mAb), or Th17 and Tfh (CCR6 mAb), followed by immune restoration/regulation with beneficial bacterial metabolites that boost Tregs and promote tolerance. This step involves use of HAMS (high amylose maize starch) diets that produce very large amounts of gut butyrate or acetate. This approach has worked spectacularly well in our hands for diabetes in the NOD mouse. Our second goal is to modulate TLR7, critical for GC formation, and prevent disease in female ARE–/– mice; TLR7 is highly expressed in female ARE–/– mice. These data may lead to future opportunities using small molecules that target TLR7 signaling. In our third and final aim we propose that inhibition of type I IFN receptor signaling will be therapeutic. We know that deletion of the type I IFN receptor in ARE–/– mice reduces disease severity. Thus, we will block the IFN receptor with a mAb and JAK/STAT signaling with a JAK inhibitor. Collectively we submit that this proposal is innovative, likely to lead to better therapeutic approaches, and has importance not only in PBC but generically in other autoimmune diseases.
期刊论文(8)
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科研奖励(0)
会议论文
DOI: 10.1016/j.autrev.2021.102804
发表时间: 2021-05
期刊: Autoimmunity reviews
影响因子: 13.6
作者: [Zhou X, Motta F, Selmi C, Ridgway WM, Gershwin ME, Zhang W]
通讯作者: Zhang W
DOI: 10.1053/j.gastro.2021.02.061
发表时间: 2021-06
期刊: Gastroenterology
影响因子: 29.4
作者: [Asselta R, Paraboschi EM, Gerussi A, Cordell HJ, Mells GF, Sandford RN, Jones DE, Nakamura M, Ueno K, Hitomi Y, Kawashima M, Nishida N, Tokunaga K, Nagasaki M, Tanaka A, Tang R, Li Z, Shi Y, Liu X, Xiong M, Hirschfield G, Siminovitch KA, Canadian-US PBC Consortium, Italian PBC Genetics Study Group, UK-PBC Consortium, Japan PBC-GWAS Consortium, Carbone M, Cardamone G, Duga S, Gershwin ME, Seldin MF, Invernizzi P]
通讯作者: Invernizzi P
DOI: 10.4049/jimmunol.2300016
发表时间: 2023-06-01
期刊: Journal of immunology (Baltimore, Md. : 1950)
影响因子: --
作者: [Zhang W, Mackay CR, Gershwin ME]
通讯作者: Gershwin ME
DOI: 10.1016/j.autrev.2021.102942
发表时间: 2021-11
期刊: AUTOIMMUNITY REVIEWS
影响因子: 13.6
作者: [Chen, Zhilei, Zhang, Weici, Selmi, Carlo, Ridgway, William M., Leung, Patrick S. C., Zhang, Fengchun, Gershwin, M. Eric]
通讯作者: Gershwin, M. Eric
7
    New Therapy for the Treatment of Primary Biliary Cholangitis.
    • 批准号:
      10697484
    • 项目类别:
    • 资助金额:
      $44.81万
    • 财政年份:
      2023
    • 负责人:
      MERRILL E GERSHWIN
    • 依托单位:
    Mechanistically based therapeutic strategies in murine primary biliary cholangitis
    • 批准号:
      10337052
    • 项目类别:
    • 资助金额:
      $39.74万
    • 财政年份:
      2020
    • 负责人:
      MERRILL E GERSHWIN
    • 依托单位:
    IDENTIFICATION OF COMMON AND UNCOMMON GENE VARIANTS IN PBC
    • 批准号:
      8334049
    • 项目类别:
    • 资助金额:
      $62.68万
    • 财政年份:
      2011
    • 负责人:
      MERRILL E GERSHWIN
    • 依托单位:
    IDENTIFICATION OF COMMON AND UNCOMMON GENE VARIANTS IN PBC
    • 批准号:
      8529510
    • 项目类别:
    • 资助金额:
      $61.78万
    • 财政年份:
      2011
    • 负责人:
      MERRILL E GERSHWIN
    • 依托单位:
    海外基金