Mechanisms of microcystin-induced hepatocellular carcinoma in nonalcoholic steatohepatitis
非酒精性脂肪性肝炎微囊藻毒素诱发肝细胞癌的机制
基本信息
- 批准号:10515346
- 负责人:
- 金额:$ 42.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-19 至 2025-10-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAccelerationAddressAgeAlcoholsAlgaeAnimalsAttenuatedAutomobile DrivingAwardBig DataCareer MobilityCell NucleusCellsCertificationCholesterolChronic DiseaseCirrhosisCoculture TechniquesComplementCountryCyanobacteriumCyanotoxinDNA MethylationDataDevelopmentDietDiethylnitrosamineDifferentiation AntigensDissectionDoseEnvironmental HealthEuthanasiaExposure toFatty acid glycerol estersFibrosisFresh WaterGenesHepatocyteHistopathologyHumanIn VitroIndividualInjectionsIntakeLiverLiver diseasesLong-Term EffectsMalignant neoplasm of liverMeasuresMediatingMicrofluidicsModelingNational Institute of Environmental Health SciencesPathogenicityPathologistPathologyPathway interactionsPersonsPhenotypePredispositionPrimary Malignant Neoplasm of LiverPrimary carcinoma of the liver cellsProtein InhibitionProtein phosphataseProteomicsProto-Oncogene Proteins c-aktRattusResearchRoleScienceScientistSprague-Dawley RatsStrategic PlanningTestingToxinUnhealthy Dietbiological researchcarcinogenesiscarcinogenicitycell determinationcell typechronic liver diseasecyanoginosin LRdefined contributiondietary constituentdietary controldruggable targetin vivoinhibitorinnovationmicrocystinnon-alcoholic fatty liver diseasenonalcoholic steatohepatitisnovelphosphoproteomicssingle nucleus RNA-sequencingstellate cellstem cell biomarkerstranscriptomicstreatment grouptumor initiatorsuptake
项目摘要
Microcystin-LR (MCLR) is the most potent and abundant cyanotoxin produced by freshwater blue-green algae.
MCLR exposure is associated with nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma
(HCC). NAFLD has quickly risen to become the most common chronic liver disease in many countries, and HCC
is the most common type of primary liver cancer. My K99/R00 data indicate MCLR drives progression of
nonalcoholic steatohepatitis (NASH), an advanced form of NAFLD, to a more severe burnt out phenotype
(increased fibrosis and reduced steatosis). The burnt out stage is an important pathogenic step towards
irreversible cirrhosis and HCC. Preliminary data in Sprague Dawley rats indicate that MCLR-elicited burnt out
NASH persists 4 weeks after MCLR exposure, in contrast to the control diet group that returned to a baseline
phenotype. In addition, MCLR persistently dysregulated matrisome genes (related to fibrosis) and
carcinogenesis genes (de-differentiation/stem cell markers) in NASH. Based on these data we hypothesize
MCLR-mediated fibrotic and carcinogenic reprogramming of the liver is enhanced in NASH and promotes the
development of cirrhosis and HCC. This hypothesis will be tested in two aims. Aim 1 will determine the role of
the protein phosphatase 2A (PP2A)-associated pathways in MCLR-mediated stellate cell activation and
hepatocyte de-differentiation. Considering the liver is the primary target for MCLR, there is surprising paucity of
research investigating these pathways and none have examined the cell type specific effects of PP2A. STUDY
1.1 will define the contribution of specific PP2A-associated pathways responsible for MCLR-elicited hepatocyte
and stellate effects using MCLR and PP2 modulators in human HepaRG hepatocytes and human LX2 stellate
cells co-cultured as 3D spheroids in static culture or microfluidics. STUDY 1.2 will test the hypothesis that
hepatocytes are the primary MCLR target and stellate cells are activated by hepatocyte damage using HepaRG
and LX2 cells cultured individually or in combination in transwell plates. STUDY 1.3 will define the effects of PP2A-
pathway modulators on MCLR- and NASH diet-elicited liver pathology in rats fed either a control or a NASH diet.
Aim 2 will determine the mechanisms and long-term effects of MCLR-elicited fibrotic and carcinogenic
reprogramming on cirrhosis and HCC development in healthy versus NASH. STUDY 2.1 will mimic important
aspects of the original MCLR tolerable daily intake study including the dose (40 µg/kg), interval (daily), and
duration (3 months) in the context of a tumor initiator (diethylnitrosamine) and a NASH diet. These mechanistic
studies will be complemented with phosphoproteomics and single nuclei transcriptomics analyses, potentially
providing druggable targets. This research will have sustained impact because it will be the first to
comprehensively assess MCLR-elicited cirrhosis and HCC in pre-existing liver disease. By mimicking the TDI
study, this research may indicate a lower TDI is required for people with pre-existing liver disease.
微囊藻毒素(microcytin - lr, MCLR)是淡水蓝绿藻产生的最有效、最丰富的藻毒素。
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)
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John Daniel Clarke其他文献
John Daniel Clarke的其他文献
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{{ truncateString('John Daniel Clarke', 18)}}的其他基金
Mechanisms of microcystin-induced hepatocellular carcinoma in nonalcoholic steatohepatitis
非酒精性脂肪性肝炎微囊藻毒素诱发肝细胞癌的机制
- 批准号:
10330468 - 财政年份:2021
- 资助金额:
$ 42.08万 - 项目类别:
Mechanisms of microcystin-induced hepatocellular carcinoma in nonalcoholic steatohepatitis
非酒精性脂肪性肝炎微囊藻毒素诱发肝细胞癌的机制
- 批准号:
10116789 - 财政年份:2021
- 资助金额:
$ 42.08万 - 项目类别:
Enteric and hepatic transporter mechanisms for pharmacokinetic natural product-drug interactions
药代动力学天然产物-药物相互作用的肠和肝转运机制
- 批准号:
10226905 - 财政年份:2020
- 资助金额:
$ 42.08万 - 项目类别:
Microcystin-LR toxicity in nonalcoholic steatohepatitis
微囊藻毒素-LR 对非酒精性脂肪性肝炎的毒性
- 批准号:
9424932 - 财政年份:2017
- 资助金额:
$ 42.08万 - 项目类别:
Microcystin-LR toxicity in nonalcoholic steatohepatitis
微囊藻毒素-LR 对非酒精性脂肪性肝炎的毒性
- 批准号:
9139475 - 财政年份:2015
- 资助金额:
$ 42.08万 - 项目类别:
Microcystin-LR toxicity in nonalcoholic steatohepatitis
微囊藻毒素-LR 在非酒精性脂肪性肝炎中的毒性
- 批准号:
8890996 - 财政年份:2015
- 资助金额:
$ 42.08万 - 项目类别:
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