Mechanism of Proteotoxicity and Experimental Therapeutic Approaches in Porphyria
卟啉症的蛋白质毒性机制和实验治疗方法
基本信息
- 批准号:10445775
- 负责人:
- 金额:$ 49.62万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-20 至 2023-02-28
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsAcuteAcute Intermittent PorphyriaAlcohol consumptionAminolevulinic AcidAnimal ModelBiochemicalBone Marrow TransplantationBrainCell Culture TechniquesDataDeferoxamineDetectionDiseaseDisease ProgressionDrug Metabolic DetoxicationDrug ModelingsDrug ScreeningDrug usageEnzymesErythropoietic PorphyriaErythropoietic ProtoporphyriaEventExcretory functionExperimental ModelsGeneticGenetic DiseasesGlycineGoalsHemeHepatitis CIn VitroIndividualInfectionInvestigational TherapiesKeratinKnowledgeLeadLead PoisoningLightLiverLiver diseasesMediatingMethionineMolecularMolecular ProfilingMolecular WeightMonitorMusMutationOrganOxidative StressOxidesOxidoreductasePathway interactionsPatientsPharmaceutical PreparationsPhotosensitivityPigmentsPorphyriasPorphyrinsPropionatesProteinsProteomicsReactive Oxygen SpeciesRoleSkinSodium Dodecyl SulfateTechnologyTestingTherapeuticTissuesToxic effectToxinUroporphyrinsWorkZebrafishbasebonecarboxylatecell injuryconstitutive androstane receptordimerdrug candidateend stage liver diseaseferrochelatasehigh throughput screeningimprovedin vivo Modelliver injurymethionine sulfoxidemethionine sulfoxide reductasemonomermouse modelnovelnovel therapeuticsoxidationpre-clinicalpreclinical studypreventprotein aggregationproteotoxicityprotoporphyrin IXrepairedsmall moleculesuccesssuccinyl-coenzyme Atissue injurytool
项目摘要
Project Summary
 Porphyrias are genetic disorders caused by mutations in enzymes involved in eight sequential biosynthetic
conversions that combine glycine and succinyl coenzyme-A in the first enzymatic step to ultimately generate
heme. Porphyrin accumulation also occurs in ‘secondary porphyrias’ in association with other diseases such as
hepatitis C virus infection. Current major unmet needs with regard to the porphyria disorders include: (a) our
present limited understanding of the biochemical mechanism of cell and tissue injury, (b) the molecular triggers
of porphyria acute attacks, (c) the reasons why some individuals develop significant organ complications such
as end-stage liver disease that requires liver or bone marrow transplantation, while others do not, and (d) the
limited availability of drugs to treat the different porphyrias. Our central hypothesis is that the liver is susceptible
to light-independent porphyrin-mediated proteotoxic damage that leads to cell and tissue injury in porphyria, and
that drugs can be identified that lead to increased or decreased porphyrin accumulation. This hypothesis will be
tested by pursuing three interconnected specific aims: (i) Define the mechanism of light-independent porphyrin-
induced protein aggregation in internal organs, with a focus on the liver; (ii) Elucidate the mechanism of
detoxification of porphyrin-induced proteotoxic damage using in vitro and in vivo models; and (iii) Characterize
small molecules that decrease or increase tissue porphyrin accumulation and porphyrin-mediated proteotoxicity.
We have assembled extensive preliminary results to support the likely success of our aims, including substantial
evidence for porphyrin-mediated protein aggregation that is light-independent, the reversibility of protein
aggregation and enzymes that are likely to be involved in reversing protein oxidation, and the use of zebrafish
high-throughput screening to identify known drugs that decrease or increase porphyrin accumulation in liver. The
drugs that decrease porphyrin accumulation will be tested for their mechanism of action and examined in
preclinical porphyria experimental models as drugs that may be repurposed as potential new therapies. In
parallel, drugs that increase porphyrin accumulation will be characterized as potential candidate drugs to avoid
in patients with porphyria.
 Completion of our proposed aims provides fundamental knowledge regarding which proteins are prone to
porphyrin-mediated oxidation and aggregation, the molecular signatures that define such aggregation, the
mechanism of aggregate turnover and disaggregation, whether compounds we characterize are candidates for
testing in patients with porphyria, and whether currently used drugs in non-porphyria disorders might need to be
avoided or monitored in patients with porphyria. This proposal uses state-of-the-art technologies, multiple
biochemical and porphyria animal model tools including zebrafish and mice, and introduces the novel concept
of proteotoxicity as an alternative mechanism for porphyria exacerbations and progression that may shed light
on genetic modifiers that account for liver disease progression in some patients but not others.
项目总结
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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{{ truncateString('Bishr Omary', 18)}}的其他基金
Mechanism of Proteotoxicity and Experimental Therapeutic Approaches in Porphyria
卟啉症的蛋白质毒性机制和实验治疗方法
- 批准号:9469835 
- 财政年份:2017
- 资助金额:$ 49.62万 
- 项目类别:
Mechanism of Proteotoxicity and Experimental Therapeutic Approaches in Porphyria
卟啉症的蛋白质毒性机制和实验治疗方法
- 批准号:9753724 
- 财政年份:2017
- 资助金额:$ 49.62万 
- 项目类别:
Mechanism of Proteotoxicity and Experimental Therapeutic Approaches in Porphyria
卟啉症的蛋白质毒性机制和实验治疗方法
- 批准号:10588162 
- 财政年份:2017
- 资助金额:$ 49.62万 
- 项目类别:
Michigan IRACDA: Training Future Professors of Engineering and Physiology
密歇根 IRACDA:培训未来的工程和生理学教授
- 批准号:9900910 
- 财政年份:2016
- 资助金额:$ 49.62万 
- 项目类别:
Michigan IRACDA: Training Future Professors of Engineering and Physiology
密歇根 IRACDA:培训未来的工程和生理学教授
- 批准号:9324272 
- 财政年份:2016
- 资助金额:$ 49.62万 
- 项目类别:
Pathogenesis of Keratin-Containing Inclusions in Liver Disease
肝脏疾病中含角蛋白包涵体的发病机制
- 批准号:7905576 
- 财政年份:2009
- 资助金额:$ 49.62万 
- 项目类别:
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