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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：
Bishr Omary
金额：
$ 49.62万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
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：
https://reporter.nih.gov/project-details/10445775
关键词：
Abbreviations Acute Acute Intermittent Porphyria Alcohol consumption Aminolevulinic Acid Animal Model Biochemical Bone Marrow Transplantation Brain Cell Culture Techniques Data Deferoxamine Detection Disease Disease Progression Drug Metabolic Detoxication Drug Modelings Drug Screening Drug usage Enzymes Erythropoietic Porphyria Erythropoietic Protoporphyria Event Excretory function Experimental Models Genetic Genetic Diseases Glycine Goals Heme Hepatitis C In Vitro Individual Infection Investigational Therapies Keratin Knowledge Lead Lead Poisoning Light Liver Liver diseases Mediating Methionine Molecular Molecular Profiling Molecular Weight Monitor Mus Mutation Organ Oxidative Stress Oxides Oxidoreductase Pathway interactions Patients Pharmaceutical Preparations Photosensitivity Pigments Porphyrias Porphyrins Propionates Proteins Proteomics Reactive Oxygen Species Role Skin Sodium Dodecyl Sulfate Technology Testing Therapeutic Tissues Toxic effect Toxin Uroporphyrins Work Zebrafish base bone carboxylate cell injury constitutive androstane receptor dimer drug candidate end stage liver disease ferrochelatase high throughput screening improved in vivo Model liver injury methionine sulfoxide methionine sulfoxide reductase monomer mouse model novel novel therapeutics oxidation pre-clinical preclinical study prevent protein aggregation proteotoxicity protoporphyrin IX repaired small molecule success succinyl-coenzyme A tissue injury tool

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