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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744772
• 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.

在哺乳动物中，大多数大多数TP结合盒（ABC）中的大多数成员可以在哺乳动物的大多数成员中获得内源性的维持和外源获得的生物。 （胃肠道）重新（肾脏），或者征集内部组织边界的那些，它们限制了墓地的摄取，并渗透到santoary组织中，鼻脊髓屏障，血液脊髓屏障，血液测试屏障）。 P-糖蛋白是一种多化学转运蛋白，可为癌细胞和多氧化型耐药性（MXR对水生生物）赋予多药耐药性（MDR）。了解P- GP功能，并在整个生物体中重新添加内源性毒性。 -GP功能将在严重性的避难所屏障中进行检查；庇护组织中的p-gp，2）定格机制在totosts中使用的p-gp内源性底物基础，4）确定是否存在P- GP和MRP调节之间的关系，以及5），以确定功能性的SAINTUE SAINTUE TIRSUE障碍物对GP的记录和新研究的贡献。先验的划分认为内源性和外源化学物质的有毒动力学，以及5）有助于模型开发，以促进转运蛋白起主要作用的动物和人类疾病的治疗。