Physiological function of P-glycoprotein in sanctuary tissue barriers in teleosts

P-糖蛋白在硬骨鱼保护区组织屏障中的生理功能

• 批准号: RGPIN-2020-04905
• 负责人: Kennedy, Christopher
• 金额: $ 3.42万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=717456
• 关键词: Physiological; function; glycoprotein; sanctuary; tissue

The maintenance of appropriate concentrations of endogenously produced, and exogenously acquired, molecules is an essential regulatory function in organisms. Prevention of their over-accumulation can be achieved through chemical translocation across biological membranes by most members of the large ATP-binding cassette (ABC) gene family. In mammals, ABC efflux transporters show predominant expression in tissues involved in absorption (gastrointestinal tract), secretion/excretion (kidney), or those that constitute internal tissue boundaries, where they limit chemical uptake and penetration into sanctuary tissues (maternalfetal barrier, blood-brain barrier, bloodcerebral spinal fluid barrier, blood-testes barrier). The 170 kDa protein P-glycoprotein is a multi-chemical resistance transporter that confers multidrug resistance (MDR) to cancer cells and multixenobiotic resistance (MXR) to aquatic organisms. Very little information exists on P-gp function in various sanctuary tissues of fish including the barriers protecting the brain and gonads. Defining a common pharmacore, particularly for endogenous compounds in sanctuary tissues, is necessary to begin to understand P-gp function, and the resulting effects on endogenous chemical toxicokinetics in whole organisms. Equally limited, is information regarding P-gp regulation and signaling pathways for induction in these and other tissues. Whole organisms, isolated tissues and isolated cells will be used in experiments to examine the physiological significance of normal P-gp function (i.e. not involving xenobiotics) in several sanctuary tissues. The substrate base, constituitive protein levels and activity, induction, regulation and signaling pathways with regard to P-gp function will be examined in several sanctuary tissue barriers; these are the primary interfaces between the peripheral circulation and the CNS/gonads of vertebrates (blood-brain, blood-testes, blood-ovary barriers). This research has several aims: 1) to assess the physiological roles of P-gp in sanctuary tissues, 2) to elucidate the regulatory mechanisms underlying P-gp expression (and MRP transporters), 3) increase knowledge regarding the teleost P-gp endogenous substrate base in teleosts, 4) to determine if a relationship exists between P-gp and MRP regulation, and 5) to determine the functional significance of sanctuary tissue barriers in teleosts and the contributions made to it by P-gp. This novel research will have significance in several areas: 1) increase knowledge regarding chemical transport physiology in teleosts, 2) understand the relevance of transport physiology chemical ecology, ecotoxicology, and life history, 3) provide insight into the sanctuary tissue barriers , 4) facilitate a priori predictions regarding the toxicokinetics of endogenous and exogenous chemicals, and 5) aid in model development to facilitate the treatment of animal and human diseases in which these transporters play a major role.

维持内源产生和外源获得的分子的适当浓度是生物体的重要调节功能。 大型 ATP 结合盒 (ABC) 基因家族的大多数成员可以通过跨生物膜的化学易位来防止其过度积累。 在哺乳动物中，ABC 外排转运蛋白在参与吸收（胃肠道）、分泌/排泄（肾脏）或构成内部组织边界的组织中表现出主要表达，在这些组织中它们限制化学物质的吸收和渗透到避难所组织（母体胎儿屏障、血液-脑屏障、血脑脊液屏障、血睾屏障）。 170 kDa 蛋白 P-糖蛋白是一种多化学耐药性转运蛋白，可赋予癌细胞多药耐药性 (MDR) 和水生生物多外源生物耐药性 (MXR)。 关于鱼类各种庇护组织（包括保护大脑和性腺的屏障）中 P-gp 功能的信息非常少。 定义一个共同的药效学，特别是对于保护区组织中的内源性化合物，对于开始了解 P-gp 功能以及由此产生的对整个生物体内源性化学毒代动力学的影响是必要的。同样有限的是有关这些组织和其他组织中 P-gp 调节和诱导信号通路的信息。 整个生物体、分离的组织和分离的细胞将用于实验，以检查几个庇护组织中正常 P-gp 功能（即不涉及外源性物质）的生理意义。将在几个庇护组织屏障中检查与 P-gp 功能相关的底物基础、组成蛋白水平和活性、诱导、调节和信号传导途径；这些是脊椎动物的外周循环和中枢神经系统/性腺（血脑、血睾丸、血卵巢屏障）之间的主要界面。 这项研究有几个目的：1) 评估 P-gp 在保护区组织中的生理作用，2) 阐明 P-gp 表达（和 MRP 转运蛋白）的调节机制，3) 增加有关硬骨鱼 P-gp 内源性的知识硬骨鱼中的底物基础，4) 确定 P-gp 和 MRP 调节之间是否存在关系，以及 5) 确定硬骨鱼中保护区组织屏障的功能意义及其贡献由 P-gp 提供。 这项新颖的研究将在几个领域具有重要意义：1）增加有关硬骨鱼化学运输生理学的知识，2）了解运输生理学化学生态学、生态毒理学和生活史的相关性，3）提供对保护区组织屏障的深入了解，4）促进有关内源性和外源性化学物质毒代动力学的先验预测，5）帮助模型开发，以促进这些转运蛋白在其中发挥主要作用的动物和人类疾病的治疗。