Vaults as New Targets for Modulating Tumor Response

拱顶是高度保守的细胞质核糖核蛋白颗粒，被认为参与了核胞质的运输。本方案的目的是探讨拱顶介导的多药耐药(MDR)的机制，以确立该颗粒作为开发抗拱顶疗法的直接靶点。多药耐药是暴露于化疗中的肿瘤细胞逃避死亡的一种常见机制。为了开发下一代癌症治疗方法，有必要了解多药耐药的机制。耐药可以通过诱导P-糖蛋白、多药耐药蛋白和乳腺癌耐药蛋白等转运相关蛋白、基本核酶、DNA拓扑异构酶的改变以及肺耐药相关蛋白(LRP)的诱导来实现，这些蛋白被认为是主要的拱顶蛋白(MVP)。将使用许多方法，包括抗MVP核酶的表达，药物核转运的干扰，以及拱顶功能受损对肿瘤发展和耐药性的影响。如果降低癌细胞中的vault水平能够阻止或逆转化疗引起的多药耐药的发展，将为vault研究开辟一个新的领域，从而导致抗vault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.