Vaults as New Targets for Modulating Tumor Response

穹窿是高度保守的细胞质核糖核蛋白颗粒，被认为参与核质运输。本提案的目的是研究穹窿介导的多药耐药（MDR）的机制，以建立作为开发抗穹窿疗法的直接靶点的颗粒。MDR是暴露于化疗的肿瘤细胞逃避死亡的常见机制。为了开发下一代癌症疗法，有必要了解MDR的机制。耐药性可通过诱导转运相关蛋白（如P-糖蛋白、多药耐药蛋白和乳腺癌耐药蛋白）、必需核酶、DNA拓扑异构酶的改变以及诱导肺耐药相关蛋白（LRP）（鉴定为主要穹窿蛋白（MVP））来实现。将使用许多方法，包括抗MVP核酶的表达、药物核转运的扰动以及受损的穹窿功能对肿瘤发展和抗性的影响。如果癌细胞中穹窿蛋白水平的降低能够预防或逆转化疗反应中产生的MDR的发展，这将开辟穹窿蛋白研究的新领域，从而导致抗穹窿蛋白调节剂的开发。

Vaults are highly conserved cytoplasmic ribonucleoprotein particles believed to be involved in nuclearcytoplasmic transport. The aim of present proposal is to investigate the mechanism of vault-mediated multidrug resistance (MDR) to establish the particle as a direct target for development of anti-vault therapeutics. MDR is a common mechanism used by tumor cells exposed to chemotherapy to escape death. In order to develop the next generation of cancer therapies it will be necessary to understand the mechanisms responsible for MDR. Drug resistance can be accomplished by induction of transport-associated proteins such as P- glycoprotein, multidrug resistance protein, and breast cancer resistance protein, alterations in the essential nuclear enzymes, DNA topoisomerases, and induction of lung resistance-related protein (LRP), identified as the major vault protein (MVP). A number of approaches will be used including expression of anti-MVP ribozymes, perturbation of nuclear transport of drugs and effects of impaired vault function on tumor development and resistance. If the reduction of vault levels in cancer cells is able to prevent or revert the development of MDR that develops in response of chemotherapy, it would open up a new areas of vault research leading to the development of anti-vault modulators.