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: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=740285
• 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 (maternal-fetal barrier, blood-brain barrier, blood-cerebral 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.

维持适当浓度的内源性产生的和外源性获得的分子是生物体的基本调节功能。通过大ATP结合盒（ABC）基因家族的大多数成员跨生物膜的化学易位，可以防止它们的过度积累。 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）的组织或构成内部组织边界的组织中显示出主要表达，在这些组织中，它们限制化学品摄取和渗透到保护区组织（母胎屏障、血脑屏障、血脑脊髓液屏障、血睾丸屏障）中。 P-糖蛋白是一种分子量为170 kDa的多化学抗性转运蛋白，可使癌细胞产生多药耐药（MDR），使水生生物产生多异源生物素耐药（MXR）。 定义一个共同的药效，特别是内源性化合物在圣所组织，是必要的开始了解P-糖蛋白的功能，并在整个生物体的内源性化学毒物代谢的影响。同样有限的，是关于P-gp的调节和信号传导途径的诱导在这些和其他组织的信息。 整个生物体、分离的组织和分离的细胞将用于实验，以检查几种保护区组织中正常P-gp功能（即不涉及外源性物质）的生理学意义。将在几种保护区组织屏障中检查P-gp功能的底物基础、组成性蛋白水平和活性、诱导、调节和信号传导途径;这些屏障是外周循环与脊椎动物CNS/性腺之间的主要界面（血脑屏障、血睾丸屏障、血卵巢屏障）。 这项研究有几个目标：1）评估P-gp在保护区组织中的生理作用，2）阐明P-gp表达的调控机制（和MRP转运蛋白），3）增加关于硬骨鱼P-gp内源性底物基础的知识，4）确定P-gp和MRP调节之间是否存在关系，（5）确定硬骨鱼类保护区组织屏障的功能意义以及P-gp对保护区组织屏障的贡献。 这项新的研究将在几个领域具有重要意义：1）增加关于硬骨鱼类中化学运输生理学的知识，2）理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）提供对避难所组织屏障的洞察，4）促进关于内源性和外源性化学物质的毒性动力学的先验预测，和5）有助于模型开发以促进这些转运蛋白在其中起主要作用的动物和人类疾病的治疗。