Sumoylation: A Novel Mechanism for Regulating Drug/Xenobiotic Transporters OATs

项目摘要 有机阴离子转运蛋白（OAT）介导多种物质的吸收、分布和排泄 环境毒素和临床上重要的药物，包括抗癌药物，抗病毒药物， 利尿剂、抗生素、抗高血压药和抗炎药。OAT在哺乳动物中大量表达， 肾脏肝脏大脑和胎盘这些器官中的OAT功能障碍显著有助于肾脏， 肝脏、神经系统和胎儿毒性和疾病。我们的长期目标是确定 通过OAT途径进行药物处置的潜在机制。在上一个赠款期间， 取得了重大进展和生产力，这一时期的新发现导致 在这一竞争性的更新中建立一个微调的研究计划和战略。我们建议 测试新的假设，即通过SUMO缀合对OAT进行翻译后修饰是一种 控制转运蛋白的稳定性、亚细胞定位和活性的重要手段。三 具体目标已列出。在具体目标I中，我们将确定OAT类小泛素化的性质。在特定 目的二，我们将评估类小泛素化在OAT介导的药物转运中的作用。在 具体目标III，我们将评估类小泛素化的生理和病理生理相关性， OAT介导的药物转运。生物化学和分子生物学的结合方法将是 用于在培养细胞、组织切片和动物中进行的拟议研究。了解 SUMO化在OAT调控中的作用是药物转运领域的一个新的研究热点， 对未来设计旨在最大化治疗效果和最小化 毒性，并将允许深入了解肾，肝， 神经和胎儿毒性和疾病。

Project Summary Organic anion transporters (OATs) mediate the absorption, distribution, and excretion of a diverse array of environmental toxins, and clinically important drugs, including anti-cancer drugs, anti-viral agents, diuretics, antibiotics, anti-hypertensives, and anti-inflammatories. OATs are abundantly expressed in kidney, liver, brain, and placenta. OAT dysfunction in these organs significantly contributes to the renal, hepatic, neurological, and fetal toxicity and disease. Our long-term goal is to define the molecular mechanisms underlying drug disposition through OAT pathway. During the previous grant period, significant progress and productivity have been achieved, and the new findings from this period led to the establishment of a fine-tuned research plan and strategy in this competing renewal. We propose to test the novel hypothesis that post-translational modification of OAT by SUMO conjugation is an important means of controlling the stability, subcellular localization, and activity of the transporter. Three Specific Aims are outlined. In Specific Aim I, we will identify the nature of OAT sumoylation. In Specific Aim II, we will assess the role of sumoylation in OAT-mediated drug transport in cultured cells. In Specific Aim III, we will evaluate the physiological and pathophysiological relevance of sumoylation in OAT-mediated drug transport. Combined approaches of biochemistry and molecular biology will be employed for the proposed studies in cultured cells, in tissue slices, and in animals. Understanding the role of sumoylation in the regulation of OATs, a novel focus in drug transport field, will have significant impact on the future design of strategies aimed at maximizing therapeutic efficacy and minimizing toxicity, and will permit insight into the molecular, cellular, and clinical bases of renal, hepatic, neurological and fetal toxicity and disease.