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:9469835
- 负责人:
- 金额:$ 45.01万
- 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 2020-07-31
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsAcuteAcute Intermittent PorphyriaAlanine TransaminaseAminolevulinic AcidAnimal ModelBinding ProteinsBiochemicalBone Marrow TransplantationCell Culture SystemCell Culture TechniquesCell DeathCell NucleusCellsChemicalsCirrhosisCoupledDeferoxamineDiseaseDisease ProgressionEndoplasmic ReticulumEnzymesErythropoietic ProtoporphyriaFatty Acid-Binding Protein 1Fatty AcidsFeverFishesGeneticGenomicsGlycineGoalsHematoxylin and Eosin Staining MethodHemeHepatitis CHereditary DiseaseIndividualInfectionInjuryIntermediate Filament ProteinsInvestigational TherapiesKeratinKnowledgeLeadLiverLiver diseasesMammalian CellMass Spectrum AnalysisMediatingMetabolicMetabolismMitochondriaModelingMolecularMorbidity - disease rateMusMutationOrganPathway interactionsPatientsPharmaceutical PreparationsPhotosensitivityPigmentsPorphyriasPorphyrinsPost-Translational Protein ProcessingPreclinical Drug EvaluationProteinsProteomicsProtoporphyrinsPublicationsReactive Oxygen SpeciesRiskRoleTechnologyTertiary Protein StructureTestingTherapeuticTissuesToxic effectTransmission Electron MicroscopyUroporphyrinsWorkZebrafishadductbiochemical modelbonecell injuryextracellularfatty acid-binding proteinsimprovedliver injurylong chain fatty acidneurotoxicitynonalcoholic steatohepatitisnovelpreventprotein Kprotein aggregateprotein aggregationproteotoxicityrelating to nervous systemsmall moleculestemsuccesssuccinyl-coenzyme Atool
项目摘要
Abstract
Porphyrias are genetic disorders caused by mutations in enzymes involved in eight sequential biosynthetic
conversions that combine glycine and succinyl coenzyme-A to generate heme. Porphyrin accumulation can
result in `secondary porphyrias' in association with other diseases such as hepatitis C virus infection. Current
major unmet needs with regard to the porphyria disorders are our present limited understanding of the
molecular triggers of porphyria acute attacks, aside from indirect association with fever or drugs; the reasons
why some individuals develop significant end-organ complications such as the need for liver or bone marrow
transplantation while others do not; and importantly the limited availability of drugs to treat the different
porphyrias. Our central hypothesis is that proteotoxic porphyrin-mediated damage, coupled with modifier
effects, contributes to the cellular damage and morbidity that is associated with porphyrias. This hypothesis
will be tested by pursuing three specific aims: (i) Define the mechanism of porphyria-induced protein
aggregation; (ii) Characterize potential modifiers that promote or protect from porphyria-induced injury in cell
culture and animal models; and (iii) Use zebrafish porphyria models to screen and characterize small-
molecule compounds that prevent tissue porphyrin accumulation. We have assembled extensive preliminary
results to support the likely success of our aims, including substantial evidence for porphyrin-mediated protein
aggregation that is dependent on the mode of porphyrin accumulation, evidence for fatty acid binding protein-
1 as a modulator of porphyrin-mediated cell and liver injury, and two novel acute zebrafish porphyria models
we generated that are amenable to high-throughput drug screening with potential positive compounds that we
propose to validate and characterize.
Completion of our proposed aims should provide fundamental knowledge regarding how porphyrins cause
protein aggregation, the subcellular compartments that are involved, whether such aggregation is due to
direct covalent porphyrin-protein adduct formation, and the mechanism of aggregate turnover. We also
anticipate being able to characterize specific porphyrin-binding proteins that regulate the propensity to
accumulate porphyrins in cells and tissues. This could provide potential clues as to why some individuals with
porphyria develop end-stage liver disease in the absence of concomitant underlying liver disorders, while
other patients are spared serious liver-related complications. Importantly, we anticipate that our proposal will
allow us to use two powerful novel acute porphyria zebrafish models we have developed to identify potential
compounds that may ultimately have therapeutic utility. This proposal uses state-of-the-art technologies,
multiple biochemical and animal model tools including zebrafish and mice, and introduces the novel concept
of proteotoxicity as an alternative mechanism for porphyria exacerbations and progression.
摘要
项目成果
期刊论文数量(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:
10445775 - 财政年份:2017
- 资助金额:
$ 45.01万 - 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:
$ 45.01万 - 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:
$ 45.01万 - 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:
$ 45.01万 - 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:
$ 45.01万 - 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:
$ 45.01万 - 项目类别:
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