EphB2 receptor tyrosine kinase in liver fibrosis
EphB2 receptor tyrosine kinase in liver fibrosis
批准号:
9766288
负责人:
Patrice Mimche
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:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-08-17 至 2021-06-30
关键词:
AffectAttenuatedAutoimmune DiseasesAutomobile DrivingBiological ProcessCellsCholestasisCicatrixCirrhosisClinical ResearchCytoplasmic TailDataDepositionDockingEph Family ReceptorsEphB2 ReceptorEphrin B ReceptorEphrinsErythropoietinEtiologyEventExcisionExtracellular MatrixFDA approvedFamilyFibrosisFutureGoalsHepatic FibrogenesisHepatic Stellate CellHepatocyteHepatologyHumanImmuneInflammationInflammatoryInjuryKnowledgeLaboratoriesLacZ GenesLigandsLigationLiverLiver CirrhosisLiver FibrosisMalariaMediatingMembraneMetabolic DiseasesMissionModelingMolecularMorbidity - disease rateMusMyofibroblastOrganOrgan failureParasitic DiseasesPathologyPathway interactionsPeptidesPharmacologyPhosphotransferasesProcessReceptor Protein-Tyrosine KinasesRecombinantsResearchRoleSignal TransductionSignaling MoleculeSiteSystemTestingTherapeutic UsesTissuesTransforming Growth Factor betaUnited States National Institutes of HealthVirus DiseasesWorkWound Healingangiogenesisbasechronic liver injurycytokinedisabilityepithelial to mesenchymal transitionfibrogenesishepatocellular carcinoma cell linehuman diseaseinflammatory milieuinnovationmacrophagemalaria infectionmembermigrationmortalitymouse modelnew therapeutic targetnovelpreventreceptorrecruittherapeutic targettraffickingtransdifferentiation
中文摘要
本申请中提出的工作确定了一种新的分子家族,即Eph受体(Erythropoietin
产生肝细胞)和它们的肾上腺素配体,可以靶向预防或逆转
肝纤维化的进展。尽管在理解分子机制方面取得了研究进展
推动肝纤维化的进展,FDA批准的治疗仍然严重受限或在某些情况下
仅限于清除病原体的病例。肝纤维化的一个特征是过度沉积
活化的肝星状细胞(HSCs)的细胞外基质成分--炎症驱动的过程
以及在损伤部位招募免疫细胞。这些免疫细胞提供了促进
炎症/纤维化微环境对静止期HSCs转分化为纤维化至关重要
肌成纤维细胞。
肝纤维化的分子基础尚不完全清楚。与细胞结合的Eph受体的连接
膜连接的肾上腺素配体启动影响多种生物的双向信号级联反应
与纤维化形成相关的过程,包括细胞重塑、血管生成、迁移/增殖和
上皮向间充质转化(EMT)。这个项目的长期目标是开发一种基于
靶向受体酪氨酸激酶EphB2治疗肝纤维化/肝硬变vbl.使用
小鼠肝纤维化模型这个探索性项目的目的是证明在肝脏中,
EphB2/ePhin-B信号通路在静止期HSCs转分化为纤维化过程中起关键作用
纤维形成过程中的肌成纤维细胞。在这项提议中检验的中心假设是,在慢性
肝损伤,HSCs上调EphB2,当与表达在不同细胞上的EPhin-B配体结合时
肝脏微环境,活化的EphB2表达的HSC启动分化过程,导致其
转化为纤维化的肌成纤维细胞。这一假设是从我们的初步数据中得出的
显示EphB2在小鼠的纤维化肝脏和人类肝硬变中都高度上调。肝星状细胞
在小鼠体内表达EphB2及其缺陷可减轻感染性和非感染性肝纤维化
模特们。在强劲的初步数据的指导下,将通过追求3个具体目标来检验中心假设:
目的1:证明肝脏需要通过EphB2的胞浆结构域进行信号传递
纤维化。
目的2:证实转化生长因子-β1对肝星状细胞EphB_2/Ephin-bs表达的调节作用。
目的3:确定靶向EphB2的治疗是否能减轻肝纤维化的形成。
据我们所知,这项极具创新性和新颖性的探索性工作是第一次调查
Eph受体在非病原体驱动的肝纤维化中的成员。这项拟议的研究具有重要意义
因为它具有巨大的翻译潜力,可以为未来的临床提供新的治疗靶点(EphB2
抗肝纤维化/肝硬变的研究。这个项目将是我自己独立实验室的最初重点。
英文摘要
The work proposed in this application identifies a novel family of molecules, the Eph receptors (Erythropoietin
producing hepatocellular) and their Ephrin ligands, that could be targeted to prevent or reverse the
progression of liver fibrogenesis. Despite research progress made in understanding the molecular mechanisms
driving the progression of hepatic fibrogenesis, FDA-approved treatments are still severely limited or in some
cases restricted to the removal of the etiologic agent. A feature of liver fibrosis is the excessive deposition of
extracellular matrix components by activated hepatic stellate cells (HSCs) a process driven by inflammation
and recruitment of immune cells at the site of injury. These immune cells provide the pro-
inflammatory/fibrogenic microenvironment critical for the transdifferentiation of quiescent HSCs into fibrogenic
myofibroblasts.
The molecular basis of liver fibrosis is incompletely understood. Ligation of cell–bound Eph receptors to
membrane-tethered ephrin ligands initiates a bi-directional signaling cascade affecting diverse biological
processes relevant to fibrogenesis including cellular remodelling, angiogenesis, migration/proliferation and
epithelial-to-mesenchymal-transition (EMT). The long-term goal of this project is to develop a therapy based
on targeting the receptor tyrosine kinase (RTK) EphB2 for the treatment of liver fibrosis/cirrhosis. Using
mouse models of liver fibrosis the objective of this exploratory project is to demonstrate that in the liver,
EphB2/ ephrin-B signaling is critical for the transdifferentiation of quiescent HSCs into fibrogenic
myofibroblasts during fibrogenesis. The central hypothesis being tested in this proposal is that upon chronic
liver injury, HSCs upregulate EphB2 and when bound to Ephrin-B ligands expressed on various cells of the
liver microenvironment, activated EphB2-expressing HSCs initiate a differentiation process leading to their
transformation into fibrogenic myofibroblasts. This hypothesis has been formulated from our preliminary data
showing that EphB2 is highly upregulated in both the fibrotic livers of mice and in human liver cirrhosis. HSCs
express EphB2 and its deficiency in mice attenuates liver fibrosis in both infectious and non-infectious
models. Guided by strong preliminary data the central hypothesis will be tested by pursuing 3 specific aims:
Aim 1: Demonstrate that signaling via the cytoplasmic domain of EphB2 is required for liver
fibrogenesis.
Aim 2: Demonstrate that TGF-β1 regulates EphB2/Ephrin-Bs expression on HSCs.
Aim 3: Determine whether therapeutic targeting EphB2 will mitigate liver fibrogenesis.
To our knowledge this highly innovative and novel exploratory work is the first to investigate the role of a
member of the Eph receptors in non-pathogen driven liver fibrogenesis. The proposed research is significant
because it has great translational potential to provide a new therapeutic target (EphB2) for future clinical
studies against liver fibrosis/cirrhosis. This project will be the initial focus of my own independent laboratory.
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会议论文
EphB/EphrinB signaling in Systemic Sclerosis
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批准号:10697360
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项目类别:
-
资助金额:$34.56万
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财政年份:2020
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负责人:Patrice Mimche
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依托单位:
EphB/EphrinB signaling in Systemic Sclerosis
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批准号:10260572
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项目类别:
-
资助金额:$33.53万
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财政年份:2020
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负责人:Patrice Mimche
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依托单位:
海外基金