STRUCT/FUNCT ANALYSIS OF ANTHRACYCLINE REDUCTION BY HUMAN CARBONYL REDUCTASE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 羰基还原酶(CR)催化一系列依赖NADPH的羰基还原反应。CR与几个重要的过程有关，包括但不限于对苯二酚的解毒、神经保护、前列腺素代谢，以及临床上感兴趣的蒽环类代谢。由于与抗药性和心脏毒性机制有关，因此降低对蒽环类药物的摄取率会显著影响其在癌症治疗中的应用。因此，CR的抑制与蒽环类药物的联合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是如何识别它结合的分子的，无论是底物还是抑制剂。有了这些信息，药物可能被设计成控制CR，目的是减少在蒽环类癌症治疗过程中的心脏毒性风险。此外，随着CR在其他途径中的作用被更好地了解，这些药物也可能被用于治疗其他疾病。

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 with 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 in other pathways is better understood, such drugs may be used to treat other diseases as well.