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：
10296811
负责人：
Xiaochao Ma
金额：
$ 33.6万
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/10296811
关键词：
ABCG2 gene Attenuated Bile fluid Binding Proteins Bone Marrow Chemicals 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 PPIX Pathway interactions Patients Phototoxicity Plasma Play Prevention Pump Role Safety Skin Specificity System Testing Therapeutic Toxic Environmental Substances Toxic effect Work analog base bile duct biliary tract common symptom cytotoxicity efficacy evaluation ferrochelatase heme biosynthesis hydrophilicity improved in vivo inhibitor/antagonist 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.

抽象的红细胞生成性原卟啉症 (EPP) 和 X 连锁原卟啉症 (XLP) 是两种遗传性疾病其特点是原卟啉 IX (PPIX) 介导的光毒性和肝毒性，并且无法治愈。该项目的目标是开发一种基于机制的策略来管理 PPIX 介导的毒性。我们的初步研究发现，ABCG2（PPIX 的外排转运蛋白）在 ABCG2 在 PPIX 介导的毒性中发挥作用，而 ABCG2 的缺乏会消除此类毒性。我们的进一步研究发现 ABCG2 缺陷会调节 PPIX 的分布和代谢。根据这些结果，我们假设抑制 ABCG2 将通过调节 PPIX 来减轻 PPIX 介导的毒性处置。为了检验我们的假设，我们提出以下具体目标：（1）开发 ABCG2 用于管理 PPIX 介导的毒性的抑制剂； (2) 确定有效性、安全性和这些新型 ABCG2 抑制剂预防 PPIX 介导的光毒性的作用机制； (3) 确定 ABCG2 抑制剂治疗的功效、安全性和作用机制 PPIX 介导的肝毒性。我们已经成功合成了28种ABCG2抑制剂，初步数据是有希望的，因为几个测试的候选者表现出强烈的 ABCG2 抑制作用活性和对抗 PPIX 介导的毒性的巨大功效。总而言之，该项目将探索 ABCG2 抑制剂治疗 PPIX 介导的光毒性的潜力肝毒性。我们还将说明抑制 ABCG2 减弱 PPIX-的机制介导的毒性。基因工程 ABCG2 和带有 ABCG2 的 EPP 小鼠模型抑制剂将用于我们提议的工作。该项目的结果将为 EPP和XLP的管理。