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The ABCG2 transporter in protoporphyrin IX disposition: from toxicity to therapy

原卟啉 IX 处置中的 ABCG2 转运蛋白：从毒性到治疗

基本信息

批准号：
10598606
负责人：
Xiaochao Ma
金额：
$ 34.06万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10598606
关键词：
ABCG2 gene Attenuated Bile fluid Binding Proteins Bone Marrow Chemicals Cholestasis Clinical Data Drug Design Drug Kinetics Drug or chemical Tissue Distribution Drug usage Enzymes Erythrocytes Erythropoietic Protoporphyria Evaluation Excretory function Genetic Diseases Genetic Engineering Heme Hepatobiliary Hepatocyte Hepatotoxicity Hydrophobicity Life Link Liver Liver Failure Malignant Neoplasms Mediating Metabolic Metabolism Pathway interactions Patients Phototoxicity Plasma Play Prevention Pump Role Safety Skin Specificity System Testing Therapeutic Toxic Environmental Substances Toxic effect Work analog bile duct biliary tract common symptom cytotoxicity efficacy evaluation ferrochelatase heme biosynthesis hydrophilicity improved in vivo inhibitor liver injury loss of function mutation metabolic profile mouse model novel novel strategies novel therapeutics prevent protoporphyrin IX public health relevance uptake

项目摘要

ABSTRACT Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are two genetic diseases characterized by protoporphyrin IX (PPIX)-mediated phototoxicity and hepatotoxicity, and there is no cure. The objective of this project is to develop a mechanism-based strategy to manage PPIX-mediated toxicities. Our preliminary studies found that ABCG2, the efflux transporter of PPIX, plays an essential role in PPIX-mediated toxicities, and deficiency of ABCG2 abolishes such toxicities. Our further studies found that ABCG2 deficiency modulates PPIX distribution and metabolism. Based on these results, we hypothesize that suppression of ABCG2 will attenuate PPIX-mediated toxicities by modulating PPIX disposition. To test our hypothesis, we propose the following specific aims: (1) to develop ABCG2 inhibitors for the management of PPIX-mediated toxicities; (2) to determine the efficacy, safety, and mechanisms of action of these novel ABCG2 inhibitors for the prevention of PPIX-mediated phototoxicity; and (3) to determine the efficacy, safety, and mechanisms of action of ABCG2 inhibitors for the treatment of PPIX-mediated hepatotoxicity. We have successfully synthesized 28 ABCG2 inhibitors, and our preliminary data are promising because several of the tested candidates showed strong ABCG2 inhibitory activity and great efficacy against PPIX-mediated toxicities. In summary, this project will explore the therapeutic potential of ABCG2 inhibitors for the management of PPIX-mediated phototoxicity and hepatotoxicity. We will also illustrate the mechanisms by which suppression of ABCG2 attenuates PPIX- mediated toxicities. Genetically engineered ABCG2 and EPP mouse models together with ABCG2 inhibitors will be used in our proposed work. The results from this project will provide a novel strategy for the management of EPP and XLP.

摘要