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
基本信息
- 批准号:8890996
- 负责人:
- 金额:$ 9.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-30 至 2017-09-29
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdultAffectAnimalsApplications GrantsArizonaBiliaryCarrier ProteinsCategoriesCellsChronicChronic Kidney FailureCommunicationComputer softwareCyanobacteriumCyclic PeptidesCysteineDataDevelopmentDevelopment PlansDietDiseaseDreamsEducational ActivitiesEducational workshopEnterocytesEnvironmentEutrophicationExcretory functionExhibitsExposure toFaceFacultyGenerationsGeneticGlutathioneGoalsGrantHealthHealth SciencesHepaticHepatocyteHepatotoxicityHumanIn VitroIncidenceIntestinesIntravenousJournalsKidneyKineticsKnock-outKnowledgeLeadLiverLiver diseasesMeasuresMediatingMembraneMentorsMetabolismMethodsMindModelingMusNational Institute of Environmental Health SciencesOATP TransportersOralOrganPathway interactionsPatientsPeer ReviewPharmaceutical PreparationsPharmacology and ToxicologyPhasePlasmaPopulationPopulations at RiskPositioning AttributePostdoctoral FellowPrevalenceProximal Kidney TubulesPublishingRattusReportingResearchResearch Project GrantsRiskRisk AssessmentRodentRouteScientistSeriesSingle Nucleotide PolymorphismSocietiesSourceSystemTechnical ExpertiseTestingTissuesToxic Environmental SubstancesToxic effectToxicant exposureToxicokineticsToxicologyToxinTrainingTraining ActivityTranslatingUnited StatesUnited States National Institutes of HealthUniversitiesWaterWorkWritingXenobiotic MetabolismXenobioticsabsorptionbasecareercareer developmentclimate changecyanobacterial toxincyanoginosin LRdisease phenotypedrinking waterenvironmental stressorexposed human populationfallsgastrointestinalhigh schoolimprovedin vivonephrotoxicitynon-alcoholic fatty livernonalcoholic steatohepatitispopulation basedpost-doctoral trainingpublic health relevanceresearch and developmentresearch studyskillssymposiumundergraduate studentuptakeurinarywaterborne
项目摘要
DESCRIPTION (provided by applicant): This pathway to independence grant application describes the training and career development plan for Dr. John Clarke. Dr. Clarke's immediate career goal is to complete the necessary postdoctoral training in order establish a research project in toxicology that is independent from the work of his post-doctoral advisor, Dr. Nathan Cherrington. This goal is directly tied to the research proposed in the application, since this project takes the liver disease phenotype studied in Dr. Cherrington's group and applies it to exposure and toxicity of an environmental stressor. Dr. Clarke's long-term career goals are to 1) improve human health by advancing our understanding of the interaction between liver disease and environmental toxicant exposure, and 2) become a mentor to subsequent generations of scientists. These immediate and long-term career goals will be accomplished through specific aspects of the training environment and the research project. Dr. Clarke's training plan includes expanding his knowledge and recognition in the field of toxicology, developing new technical expertise, improving his mentoring and communication skills, and improving grant writing skills. In order to increase knowledge and recognition in the field of toxicology Dr. Clarke will participate in educational and training activities available through the NIEHS training grant, the Society of Toxicology, the Pharmacology and Toxicology Department, and the Arizona Health Sciences Center. These include seminars, journal clubs, colloquia, and conferences. Dr. Clarke has assembled a "dream team" of mentors and collaborators that will be an incredible asset for his career development and research plan. Dr. Clarke will develop new technical expertise in xenobiotic transport kinetics, in vivo toxicokinetics analyses, organ specific toxicity, and physiologically based toxicokinetics modeling (PBTK). An important aspect of being an independent scientist is the ability to mentor and communicate effectively. As part of the training
environment Dr. Clarke will continue to present data at conferences and publish in peer-reviewed journals. He will also continue to mentor high school, graduate, and undergraduate students in Dr. Cherrington's lab. Finally, he will improve his grant writing skills by participatig in a series of grant writing workshops offered at the University of Arizona and through the NIH. By implementing each aspect of this training plan, Dr. Clarke will receive the additional training he needs to successfully transition into an independent faculty position in toxicology. This research project seeks to understand how the liver disease nonalcoholic steatohepatitis (NASH) alters the toxicokinetics and toxicity of the waterborne toxin microcystin-LR (MCLR). The prevalence of NASH, which is the most severe form of nonalcoholic fatty liver disease, continues to increase worldwide and is estimated to be present in 5% to 17% of adults in the United States. In addition to the liver problems this population faces, there is also a higher incidence of chronic kidney disease among these patients, which may be associated with MCLR exposure. MCLR-producing cyanobacteria are ubiquitous in sources of drinking water around the world, and the occurrence of blooms and MCLR contaminated drinking water are expected to increase as anthropomorphic eutrophication of water systems and global climate change continue to worsen. Unfortunately, there is a dearth of information regarding MCLR toxicokinetics in humans and how NASH-associated changes in xenobiotic transporter expression influence MCLR toxicokinetics and MCLR-induced toxicity. The objectives of this research are to 1) provide a complete picture of the xenobiotic transporters responsible for the disposition of MCLR and its main metabolites, MCLR-glutathione and MCLR-cysteine, 2) determine how altered expression of these transporters in NASH affects MCLR disposition and toxicity, and 3) move these findings towards risk assessment by constructing a PBTK model for human MCLR exposure in healthy and NASH populations. Dr. Clarke's previous work has demonstrated that NASH causes decreased expression of the liver uptake transporters important for MCLR-induced liver toxicity: organic anion transporting polypeptide-1b2 (Oatp1b2) in rodents and OATP1B1 and OATP1B3 in humans. He has also shown that this NASH-induced decrease in rodent Oatp1b2 shifted the disposition of several drugs that are substrates for OATPs away from liver exposure towards kidney exposure. In the case of MCLR, it has been shown that genetic knockout of Oatp1b2 completely protected the mice from MCLR-induced liver toxicity. In a recently completed preliminary study Dr. Clarke has shown that MCLR exposure in NASH dramatically increase kidney toxicity compared to healthy controls exposed to MCLR. These data lead to the central hypothesis that people with NASH are at increased risk of altered MCLR exposure and MCLR-induced renal toxicity due to changes in hepatic OATP transporters. To test this hypothesis and achieve the objectives of this project several methods will be employed. First, in vitro transporter kinetics experiments will be performed to identify transporters, beyond the Oatps, that contribute to MCLR disposition. Second, the effect of NASH on MCLR disposition will be determined by measuring toxicokinetics profiles after oral and intravenous MCLR administration in healthy and NASH rats. Third, acute and sub-chronic, sub-lethal toxicity studies will be performed to determine if MCLR exposure in NASH increases renal toxicity. Lastly, a PBTK model for MCLR exposure in humans will be constructed using the Simcyp software to help translate this work into exposure information for human populations. The research project outlined here is important to the development of Dr. Clarke's career but, more importantly, it is important to millions of people worldwide who have NASH and are exposed to MCLR.
描述(由申请人提供):这份独立之路资助申请描述了约翰·克拉克博士的培训和职业发展计划。克拉克博士的近期职业目标是完成必要的博士后培训,以便建立一个独立于他的博士后导师内森·切林顿博士工作的毒理学研究项目。这一目标与申请中提出的研究直接相关,因为该项目采用了Cherrington博士小组研究的肝脏疾病表型,并将其应用于环境压力源的暴露和毒性。克拉克博士的长期职业目标是:1)通过加深我们对肝病与环境毒物暴露之间相互作用的理解来改善人类健康;2)成为后辈科学家的导师。这些近期和长期的职业目标将通过培训环境和研究项目的具体方面来实现。克拉克博士的培训计划包括扩展他在毒理学领域的知识和认知度,发展新的技术专长,提高他的指导和沟通技巧,以及提高拨款写作技巧。为了提高在毒理学领域的知识和认知度,克拉克博士将参加NIEHS培训补助金、毒理学学会、药理学和毒理学部门以及亚利桑那州健康科学中心提供的教育和培训活动。这些活动包括研讨会、期刊俱乐部、座谈会和会议。克拉克博士组建了一个由导师和合作者组成的“梦之队”,这对他的职业发展和研究计划将是一笔不可思议的财富。克拉克博士将在异种生物运输动力学、体内毒性动力学分析、器官特异性毒性和基于生理的毒性动力学建模(PBTK)方面开发新的技术专长。作为一名独立科学家的一个重要方面是指导和有效沟通的能力。作为培训的一部分
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:
10515346 - 财政年份:2021
- 资助金额:
$ 9.14万 - 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:
10330468 - 财政年份:2021
- 资助金额:
$ 9.14万 - 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:
$ 9.14万 - 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:
$ 9.14万 - 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:
$ 9.14万 - 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:
$ 9.14万 - 项目类别:
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