MDR1 and Related Proteins during HIV PI Exposure

描述（由申请人提供）：脂质代谢异常和相关代谢紊乱是HIV感染的重要并发症。这些改变的机制可能与HIV本身和/或抗逆转录病毒药物治疗有关。MDR 1基因产物P-gp是决定用于治疗HIV、其并发症和相关病症（如药物滥用）的药物的处置、药代动力学和药物相互作用的重要决定因素。HIV蛋白酶抑制剂（PI）与P-gp相互作用，但来自不同实验范式的结果往往是相互矛盾的。在MDR 1活跃的各种解剖部位发生的暴露条件范围内，PI如何影响MDR 1尚未确定。PI可急性抑制MDR 1的功能，但可导致MDR 1的过度表达。各个PI对MDRI的影响能力不同。除了塑造药物底物的动力学特征外，MDR 1是一组参与脂质稳态的ABC转运蛋白之一，包括肠道中胆固醇的摄取。另一种ABC转运蛋白ABCA 1在胆固醇转运中也很重要，该基因的缺陷可导致家族性高密度脂蛋白缺乏症和丹吉尔病。MDR 1和ABCA 1在某些情况下似乎一起工作，了解PI如何影响MDR 1和ABCA 1将有助于了解PI如何影响胆固醇和其他脂质的转运。此外，MDR 1基因启动子区含有NF κ B位点，NF κ B是一种普遍存在的转录因子，在许多不同的过程中发挥作用，包括动脉粥样硬化和胰岛素抵抗。有限的数据表明利托那韦影响NFkB激活，但对于急性和慢性暴露或PI类之间是否存在差异效应知之甚少。本提案将探索PI与MDR 1之间的关系，以及与MDR 1相关的其他两种蛋白质。细胞培养模型将在生理相关PI浓度范围内检查转运蛋白mRNA、蛋白质和功能。将测定这些相同细胞中NFkB的应答。此外，将在相同条件下检查细胞培养模型中的胆固醇摄取。这些发现对于理解与PI相关的脂质紊乱以及用于治疗HIV和相关疾病的药物的动力学具有重要意义。

DESCRIPTION (provided by applicant): Abnormal lipid metabolism and associated metabolic disorders are important complications of HIV infection. The mechanism(s) underlying these alterations may be related to HIV itself and/or treatment with antiretrovirals. The MDR1 gene product P-gp is an important determinant of the disposition, pharmacokinetics and drug interactions of drugs used in the treatment of HIV, its complications, and related conditions such as drug abuse. The HIV protease inhibitors (PIs) interact with P-gp, but the results from diverse experimental paradigms are often conflicting. It is not established how the PIs affect MDR1 over the range of exposure conditions that occur at the various anatomic sites where MDR1 is active. PIs can acutely inhibit the function of MDR1 but can lead to MDR1 over expression with chronic exposure. The individual PIs differ in their ability to have an impact on MDRI. In addition to shaping the kinetic profile of drug substrates, MDR1 is one of a group of ABC transport proteins involved in lipid homeostasis, including the uptake of cholesterol in the intestine. Another ABC transporter, ABCA1, is also important in cholesterol transport, and defects in this gene can result in familial high-density lipoprotein deficiency and Tangier disease. MDR1 and ABCA1 appear to work together under certain circumstances, and knowing how the PIs affect MDR1 and ABCA1 would provide insight into how the PIs could affect transport of cholesterol and other lipids. Additionally, the MDR1 gene promoter region contains a site for NFkB, a ubiquitous transcription factor with roles in many diverse processes, including atherosclerosis and insulin resistance. Limited data indicate ritonavir affects NFkB activation, but little is known about whether there are differential effects from acute and chronic exposure or across the class of PIs. This proposal will explore the relationship between the PIs and MDR1, as well as two other proteins with relationships to MDR1. Cell culture models will examine transporter mRNA, protein and function over a range of physiologically relevant PI concentrations. The response of NFkB in these same cells will be determined. Additionally, cholesterol uptake in the cell culture model will be examined under the same conditions. The findings will be of importance in understanding lipid disorders related to PIs as well as the kinetics of drugs used to treat HIV and related disorders.