Function of the MRP Family

描述（由申请方提供）：MRP 1和MRP 2是ABC转运蛋白MRP家族的创始成员，是药物外排泵，在细胞对抗癌药物的耐药性和药物分布中发挥重要作用。这两个泵现在已知是一个多基因家族的一部分，该家族扩展到9个成员。最近在我的实验室和其他人的研究已经确定，前三个新确定的家庭成员进行检查，MRP 3，MRP 4和MRP 5，也是药物泵参与细胞耐药性抗癌剂。MRP 3是一种谷胱甘肽和葡萄糖醛酸结合物外排泵，具有赋予依托泊苷和甲氨蝶呤耐药性的功能，也可能有助于这些药物的口服生物利用度，以及在胆汁淤积性疾病期间参与肝细胞的防御，防止这些药物被挤出到胆汁中。MRP 4和MRP 5是环核苷酸外排泵，其被细胞用作核苷酸类似物如6-巯基嘌呤的抗性因子，并且MRP 4的抗性谱也包括甲氨蝶呤。这些最近的发展已经披露，该家族的新成员中至少有3个参与了与癌症化疗药物直接相关的重要领域，并提供了一个令人信服的理由，为什么该家族的每个新鉴定的成员的活性应该进行深入研究。在这次竞争性更新中，我们将扩展我们之前对MRP 4的研究，并继续分析其他新发现的家族成员。关于MRP 4，我们将确定其赋予核苷酸类似物抗性的生化机制，进一步探索其赋予癌症化疗药物抗性的潜力，并通过使用实验小鼠模型评估其作为抗性因子的体内效力。此外，我们将分析两个新发现的家族成员的耐药能力和底物选择性，这两个家族成员与MRP 4和MRP 5的结构相似性表明其功能保守或重叠，其研究可能与我们对MRP 4的同步研究协同作用。这些实验应该提供一个更完整的图片的潜力，这个复杂的家庭不寻常的泵影响癌症治疗。

DESCRIPTION (provided by applicant): MRP1 and MRP2, the founding members of the MRP family of ABC transporters, are drug efflux pumps that play prominent roles in cellular resistance to anticancer agents and in drug distribution. These two pumps are now known to be part of a multigene family that extends to 9 members. Recent studies in my laboratory and others have determined that the first three of the newly identified family members to be examined, MRP3, MRP4 and MRP5, are also drug pumps involved in cellular resistance to anticancer agents. MRP3 is a glutathione and glucuronate conjugate efflux pump that has the facility for conferring resistance to etoposide and methotrexate, and may also contribute to the oral bioavailability of these agents, as well as participate in the defense of hepatocytes during cholestatic conditions that prevent these agents from being extruded into the bile. MRP4 and MRP5 are cyclic nucleotide efflux pumps that are deployed by the cell as resistance factors for nucleotide analogs such as 6-mercaptopurine, and the resistance profile of MRP4 includes methotrexate as well. These recent developments have disclosed that at least 3 of the new members of this family are involved in important areas that relate directly to cancer chemotherapeutic agents, and provide a compelling reason why the activities of each of the newly identified members of this family should be investigated in depth. In this competitive renewal we will extend our previous investigation of MRP4 and continue our analysis of other newly identified family members. With regard to MRP4, we will determine the biochemical mechanism by which it confers resistance to nucleotide analogs, further explore its potential for conferring resistance to cancer chemotherapeutic agents, and assess its in vivo potency as a resistance factor by the use of experimental mouse models. In addition, we will analyze the drug resistance capabilities and substrates selectivities of two of the newly identified family members whose structural resemblance to MRP4 and MRP5 suggests conserved or overlapping functions and whose investigation may synergize with our concurrent studies on MRP4. These experiments should provide a more complete picture of the potential for this complex family of unusual pumps to impact cancer treatment.