STRUCT/FUNCT ANALYSIS OF ANTHRACYCLINE REDUCTION BY HUMAN CARBONYL REDUCTASE

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 羰基还原酶 (CR) 催化多种羰基的 NADPH 依赖性还原。 CR 与几个重要的过程有关，包括但不限于醌解毒、神经保护、前列腺素代谢，以及具有临床意义的蒽环类药物代谢。蒽环类药物的 CR 降低显着影响其在癌症治疗中的使用，因为它与耐药性和心脏毒性机制有关。因此，抑制 CR 与蒽环类药物治疗相结合，有可能提高药物的有效性并降低相关心脏毒性的风险。这项工作的重点是更好地了解 CR 如何识别与其结合的分子，无论是底物还是抑制剂。配备此信息后，可以设计药物来控制 CR，以降低蒽环类癌症治疗期间心脏毒性的风险。此外，由于 CR 的作用是更好地了解其他途径，因此此类药物也可用于治疗其他疾病。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Carbonyl reductase (CR) catalyzes the NADPH-dependent reduction of a wide range of carbonyls. CR has been connected to several important processes including but not limited to quinone detoxification, neuroprotection, prostaglandin metabolism, and, of clinical interest, anthracycline metabolism. CR reduction of anthracyclines significantly impacts their use in the treatment of cancer as it has been linked to both drug resistance and cardiotoxicity mechanisms. Therefore, inhibition of CR in conjunction with anthracycline therapy offers the potential both to increase the effectiveness of the drugs and to decrease the risk of the associated cardiotoxicity. The major emphasis of this work is to better understand how CR recognizes the molecules to which it binds, be they substrates or inhibitors. Equipped this information, drugs may be designed to control CR with the intention of reducing the risk of cardiotoxicity during anthracycline cancer treatment. Also, as the role of CR is other pathways is better understood such drugs may be used to treat other diseases as well.