A Model for Human Liver Fibrosis
A Model for Human Liver Fibrosis
批准号:
10685178
负责人:
GARY A PELTZ
金额:
$77.23万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-09-01 至 2024-08-31
关键词:
AddressAdhesivesAdultAnimalsAppearanceAutosomal Recessive Polycystic KidneyBiochemicalCause of DeathCellsChemicalsCirrhosisCollagenCollagen FiberCuesCytometryDataDevelopmentDiseaseDrug CombinationsEngineeringEtiologyEvaluationExtracellular MatrixFDA approvedFibrosisGenesGeneticGenetic DiseasesGenomicsHepaticHumanJoubert syndromeLigandsLiverLiver FibrosisLiver diseasesMechanicsMediatingMethodsMicroscopyModelingMonitorMutationMyofibroblastNonesterified Fatty AcidsOrganoidsOutcomePathogenesisPathologicPathway interactionsPatientsPharmaceutical PreparationsProductionPropertyResearchSchemeSynthesis ChemistrySystemTestingTherapeuticThickTimeTissuesViralantifibrotic treatmentbasecausal variantcell typechronic liver diseasechronic liver injurydrug candidatehigh dimensionalityhuman stem cellsimaging modalityinduced pluripotent stem cellinsightlive cell imagingmetabolomicsnonalcoholic steatohepatitisnovelnovel therapeuticsresponsesingle-cell RNA sequencingtranscriptomicsviscoelasticity
中文摘要
摘要
肝纤维化是由细胞外基质(ECM)积聚引起的病理状况,其响应于肝纤维化。
慢性肝损伤,是全球成人死亡的主要原因(每年约100万人),原因是治疗不足
选项.为了解决这一限制,我们开发了人类肝脏类器官模型,使假设-
用于治疗肝纤维化的新型候选药物的驱动的机制评价。其中一款车型由
工程化iPSC以表达常染色体隐性多囊肾病的常见致病突变
(ARPKD). ARPKD类器官形成肝纤维化的关键标志:它们积累厚的胶原纤维;
并且产生胶原的肌成纤维细胞显著增加,其转录组学特征与那些
存在于从患有常见的(获得性的)肝纤维化形式(病毒性的)的患者获得的肝组织中,
诱导的肝硬化和晚期非酒精性脂肪性肝炎,NASH)。我们还开发了NASH类器官
纤维化模型;沿着两种活细胞成像方法用于监测胶原纤维的外观,
产生胶原蛋白的细胞。我们假设,由于纤维化在这个人身上发展,多谱系,
肝类器官类似于先天性和获得性肝纤维化患者的肝类器官,可用于
推进肝纤维化研究并发现和表征抗纤维化疗法。在目标1中,ARPKD和
NASH类器官用于开发一种新的平台,用于评估10种药物的抗纤维化功效,
作用机制与肝纤维化相关,并确定具有增加的抗纤维化作用的药物组合。
功效由于九种药物是FDA批准的药物,但目前没有一种用于治疗肝纤维化,这些研究
可能具有重大的翻译意义。在目的2中,这些模型评估ECM的纤维化作用。
线索使用一种新的,完全化学定义,生物合成基质。ECM的变化被广泛认为是促进
纤维化重塑一种新的合成化学方案能够调节关键的机械(刚度,
粘弹性)和生物化学(细胞粘附配体特性)基质性质。ARPKD和NASH类器官
在合成基质中生长的细胞将使我们能够检查基质线索对纤维化的影响,
分析包括单细胞RNA测序(scRNA-Seq)。在目标3中,确定共同的致病驱动因素
在先天性和后天性肝纤维化之间共享,我们将我们的建模方法扩展到
生成和表征Joubert综合征相关疾病(JSRD)的类器官模型,这是一种多-
系统遗传性疾病,在某些情况下会导致肝纤维化,我们描述了一种独特的NASH类器官
模型JSRD肝病不能在动物中建模。JSRD和NASH类器官和等基因对照将
使用scRNA-Seq、高维飞行时间质谱细胞术(CyTOF)和两个半靶向的
代谢组学方法。JSRD类器官还将用于测试10种药物的抗纤维化作用(目标1),
用于表征ECM对纤维化的作用(目的2)。这些数据将提供有关共享的重要信息
介导不同病因的肝纤维化的机制。
英文摘要
Abstract
Liver fibrosis is a pathological condition that results from extracellular matrix (ECM) accumulation in response to
chronic liver injury and is a major global cause of death in adults (~1M per year) due to inadequate therapeutic
options. To address this limitation, we have developed human hepatic organoid models that enable hypothesis-
driven, mechanistic evaluation of novel drug candidates for treatment of liver fibrosis. One model is produced by
engineering iPSC to express a common causative mutation for Autosomal Recessive Polycystic Kidney Disease
(ARPKD). ARPKD organoids develop the key hallmarks of hepatic fibrosis: they accumulate thick collagen fibers;
and have a marked increase in collagen-producing myofibroblasts whose transcriptomic profile is like those
present in liver tissues obtained from patients with commonly occurring (acquired) forms of liver fibrosis (viral-
induced cirrhosis and advanced non-alcoholic steatohepatitis, NASH). We also developed a NASH organoid
fibrosis model; along with two live cell imaging methods for monitoring for the appearance of collagen fibers and
collagen producing cells. We hypothesize that since the fibrosis that develops in this human, multi-lineage,
hepatic organoid resembles that in patients with congenital and acquired forms of liver fibrosis, it can be used to
advance liver fibrosis research and to discover and characterize anti-fibrotic therapies. In Aim 1, ARPKD and
NASH organoids are used to develop a novel platform for assessing the anti-fibrotic efficacy of 10 agents whose
mechanism of action is relevant to liver fibrosis, and to identify drug combinations with increased anti-fibrotic
efficacy. Since nine are FDA-approved drugs, but none are currently used to treat liver fibrosis, these studies
could have significant translational importance. In Aim 2, these models evaluate the fibrogenic effect of ECM
cues using a novel, fully chemically defined, biosynthetic matrix. ECM changes are widely thought to promote
fibrotic remodeling. A novel, synthetic chemistry scheme enables tuning of the key mechanical (stiffness,
viscoelasticity) and biochemical (cell-adhesive ligand identity) matrix properties. ARPKD and NASH organoids
grown in synthetic matrices will enable us to examine the effects that matrix cues have on fibrosis, and this
analysis includes single cell RNA sequencing (scRNA-Seq). In Aim 3, to identify common pathogenetic drivers
that are shared among congenital and acquired forms of liver fibrosis, we extend our modeling approach to
generate and characterize organoid models for Joubert Syndrome Related Disorder (JSRD), which is a multi-
system genetic disease that causes liver fibrosis in some cases, and we characterize a unique NASH organoid
model. JSRD liver disease cannot be modeled in animals. JSRD and NASH organoids and isogenic controls will
be analyzed using scRNA-Seq, high-dimensional time of flight mass cytometry (CyTOF) and two semi-targeted
metabolomic methods. JSRD organoids will also be used to test the anti-fibrotic effects of 10 drugs (Aim 1) and
for characterizing ECM effects on fibrosis (Aim 2). This data will provide important information about shared
mechanisms that mediate liver fibrosis of different etiologies.
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