STRUCT/FUNCT ANALYSIS OF ANTHRACYCLINE REDUCTION BY HUMAN CARBONYL REDUCTASE

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH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 中心，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、前列腺素代谢以及临床感兴趣的蒽环类药物代谢。蒽环类药物的CR降低显著影响其在癌症治疗中的应用，因为它与耐药性和心脏毒性机制有关。因此，抑制CR联合蒽环类药物治疗提供了增加药物有效性和降低相关心脏毒性风险的潜力。这项工作的主要重点是更好地了解CR如何识别它所结合的分子，无论是底物还是抑制剂。配备这些信息，药物可以被设计为控制CR，目的是降低蒽环类药物治疗期间心脏毒性的风险。此外，由于CR的作用是更好地理解其他途径，因此这些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.