Development of delivery methods for combination microRNA treatment of alcohol-associated liver disease
开发联合 microRNA 治疗酒精相关性肝病的递送方法
基本信息
- 批准号:10676945
- 负责人:
- 金额:$ 38.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-01 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAlcoholic HepatitisAlcoholic Liver DiseasesAlcoholsAnimal ModelAttenuatedAziridinesBiologicalCXCR4 ReceptorsCXCR4 geneCholesterolChronicCirrhosisClinical TrialsCollagenCombined Modality TherapyComplexDataDevelopmentDiseaseDown-RegulationDrug Delivery SystemsDrug KineticsEffectivenessEncapsulatedEventExhibitsExposure toFibrosisFormulationFunctional disorderGenesGoalsHealthHepaticHepatic Stellate CellHepatocyteHumanIn VitroInflammatory ResponseKnowledgeKupffer CellsLigandsLigationLiverLiver CirrhosisLiver FibrosisLiver diseasesMacrophageMannoseMediatingMethodsMicroRNAsMicrofluidicsModelingModificationMolecular WeightMusNatural HistoryPathogenesisPathway interactionsPerformancePlayPolymersPositioning AttributeProductionPropertyPublic HealthResearchRoleSignal TransductionSliceStromal Cell-Derived Factor 1TNF geneTestingTherapeuticTherapeutic EffectTransfectionTreatment EfficacyTropismWorkalcohol abuse therapyantifibrotic treatmentattenuationbile ductchemokine receptordesignfatty liver diseaseimmunoreactionimprovedin vivo evaluationinhibitorinnovationintrahepaticliver injurymicroRNA deliverymouse modelnanoparticlenanoparticle deliverynovel therapeutic interventionoverexpressionparticlepharmacologicprototypeself assemblytargeted deliverytherapeutic evaluationtherapeutic miRNAtherapeutic target
项目摘要
PROJECT SUMMARY
Alcohol-associated liver disease (AALD) is a major and growing health concern with limited treatment options.
The natural history of AALD (formerly known as alcoholic liver disease) includes fatty liver disease, alcoholic
hepatitis and the development of fibrosis preceding end-stage cirrhosis. MicroRNAs (miRNAs) represent a new
class of therapeutics due to their ability to simultaneously affect multiple fibrosis-associated pathways. Among
possible targets, miR-155 is involved in inflammatory responses mediated by Kupffer cells (KCs) that affect
fibrogenic events in multiple other hepatic cells. Chemokine receptor CXCR4 and its cognate ligand stromal cell-
derived factor-1 play important and complex roles in the pathogenesis of AALD, including the coordination of the
initial immune reaction upon liver injury and later in controlling the progression of liver fibrosis through its
activating effect on hepatic stellate cells (HSCs) and collagen production. The goal of this project is to develop
integrated miRNA delivery platform based on self-assembled nanoparticles (polyplexes) that deliver anti-miR-
155 to activated KCs and in parallel inhibit CXCR4 signaling in activated HSCs in the liver. The delivery platform
is based on innovative CXCR4 inhibitors based on cyclam-modified low molecular weight poly(ethylenimine)s
(C-PEI) that efficiently encapsulate and systemically deliver miRNA. The objective is to test the hypothesis that
C-PEI/miRNA will lead to enhanced combination effect due to attenuation of profibrogenic signaling of both
hepatic macrophages and the matrix-producing HSCs. We will accomplish the overall objectives in three specific
aims. In Aim 1, we will optimize formulation of the C-PEI-miRNA nanoparticles that deliver anti-miR-155 in liver
fibrosis. Based on encouraging antifibrotic activity in our preliminary studies, we hypothesize that polyplex
modification with mannose and with stabilizing cholesterol moieties will result in efficient delivery of the miRNA
to activated KCs, while excess free C-PEI will target activated HSCs. In Aim 2, we will test the in vivo therapeutic
efficacy of the polyplexes in the bile-duct ligation (BDL) model and mouse models of chronic alcohol
administration with exposure to CCl4. The goal is to conduct comprehensive evaluation of therapeutic efficacy of
the optimized C-PEI-Chol/anti-miR-155 polyplexes in different models and multiple stages of fibrosis. The
findings from the mouse models will be validated in cultured human precision-cut liver slices. In Aim 3, we will
determine the mechanism of antifibrotic activity of the combined miR-155 and CXCR4 inhibition. Although our
preliminary data are consistent with miR-155 downregulation in KCs and inhibition of CXCR4 in activated HSCs,
the precise mechanism of action of the C-PEI/anti-miR-155 polyplexes is not known. Therefore, the studies in
this aim will be designed to ascertain the underlying mechanisms of action of the polyplexes. Overall, this project
will contribute to the fundamental understanding of the role and therapeutic potential of CXCR4 and miR-155
inhibition in AALD and will innovatively address targeted delivery of drug/miRNA combinations as an anti-fibrotic
treatment.
项目摘要
酒精相关性肝病(AALD)是一种主要且日益增长的健康问题,治疗选择有限。
AALD(以前称为酒精性肝病)的自然史包括脂肪肝、酒精性肝病、酒精性
肝炎和终末期肝硬化前纤维化的发展。microRNAs(miRNAs)是一种新的
由于其同时影响多种纤维化相关途径的能力,它们是一类治疗剂。之间
可能的靶点,miR-155参与库普弗细胞(KCs)介导的炎症反应,影响
多个其他肝细胞中的纤维化事件。趋化因子受体CXCR 4及其同源配体基质细胞
在AALD的发病机制中起着重要而复杂的作用,包括协调
肝损伤后的初始免疫反应,以及随后通过其
对肝星状细胞(HSC)和胶原蛋白产生的活化作用。该项目的目标是开发
基于自组装纳米颗粒(聚合复合物)的整合的miRNA递送平台,其递送抗miR-21。
155与活化的KC结合,并平行抑制肝脏中活化的HSC中的CXCR 4信号传导。外卖平台
是基于创新的CXCR 4抑制剂的基础上,环拉胺改性的低分子量聚(乙烯亚胺)
(C-PEI),其有效地包封并全身递送miRNA。目的是检验假设,
C-PEI/miRNA将由于两者的促纤维化信号传导的减弱而导致增强的组合效应。
肝巨噬细胞和产生基质的HSC。我们将从三个具体方面实现总体目标
目标。在目标1中,我们将优化在肝脏中递送抗miR-155的C-PEI-miRNA纳米颗粒的制剂
纤维化基于我们的初步研究中令人鼓舞的抗纤维化活性,我们假设复合物
用甘露糖和稳定胆固醇部分修饰将导致miRNA的有效递送
活化的KC,而过量的游离C-PEI将靶向活化的HSC。在目标2中,我们将测试体内治疗剂
复合物在胆管结扎(BDL)模型和慢性酒精小鼠模型中的功效
暴露于CCl 4。目的是综合评价
优化的C-PEI-Chol/anti-miR-155复合物在不同模型和多个纤维化阶段中的作用。的
来自小鼠模型的发现将在培养的人精确切割的肝脏切片中得到验证。在目标3中,我们
确定组合的miR-155和CXCR 4抑制的抗纤维化活性的机制。虽然我们的
初步数据与KC中miR-155下调和活化HSC中CXCR 4的抑制一致,
C-PEI/抗miR-155复合物的精确作用机制尚不清楚。因此,
该目的将被设计为确定复合物的潜在作用机制。总的来说,这个项目
将有助于从根本上理解CXCR 4和miR-155的作用和治疗潜力
抑制AALD,并将创新性地解决药物/miRNA组合作为抗纤维化药物的靶向递送。
治疗
项目成果
期刊论文数量(1)
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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BENITA L. MCVICKER其他文献
BENITA L. MCVICKER的其他文献
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{{ truncateString('BENITA L. MCVICKER', 18)}}的其他基金
Alcohol-sensitized macrophages enhance colorectal carcinoma metastasis in the liver
酒精敏感性巨噬细胞增强结直肠癌肝转移
- 批准号:
10427229 - 财政年份:2019
- 资助金额:
$ 38.9万 - 项目类别:
Development of delivery methods for combination microRNA treatment of alcohol-associated liver disease
开发联合 microRNA 治疗酒精相关性肝病的递送方法
- 批准号:
10442687 - 财政年份:2019
- 资助金额:
$ 38.9万 - 项目类别:
Alcohol-sensitized macrophages enhance colorectal carcinoma metastasis in the liver
酒精敏感性巨噬细胞增强结直肠癌肝转移
- 批准号:
10265327 - 财政年份:2019
- 资助金额:
$ 38.9万 - 项目类别:
Alcohol Alters Hepatic Immune Function: Role of the Asialoglycoprotein Receptor
酒精改变肝脏免疫功能:去唾液酸糖蛋白受体的作用
- 批准号:
8391632 - 财政年份:2011
- 资助金额:
$ 38.9万 - 项目类别:
Alcohol Alters Hepatic Immune Function: Role of the Asialoglycoprotein Receptor
酒精改变肝脏免疫功能:去唾液酸糖蛋白受体的作用
- 批准号:
8598019 - 财政年份:2011
- 资助金额:
$ 38.9万 - 项目类别:
Alcohol Alters Hepatic Immune Function: Role of the Asialoglycoprotein Receptor
酒精改变肝脏免疫功能:去唾液酸糖蛋白受体的作用
- 批准号:
8244030 - 财政年份:2011
- 资助金额:
$ 38.9万 - 项目类别:
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