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

项目摘要 有机阴离子转运体(燕麦)调节多种物质的吸收、分布和排泄。 环境毒素，以及临床重要药物，包括抗癌药物，抗病毒药物， 利尿剂、抗生素、抗高血压药和消炎药。燕麦丰富地表达在 肾脏、肝脏、大脑和胎盘。这些器官中的燕麦功能障碍对肾脏有很大的贡献， 肝脏、神经和胎儿毒性和疾病。我们的长期目标是定义分子 通过燕麦片途径处理药物的潜在机制。在前一批款期内， 已经取得了重大进展和生产力，这一时期的新发现导致 在这一竞争更新中建立微调的研究计划和战略。我们建议 检验新的假设，即通过相扑共轭对燕麦进行翻译后修饰是一种 控制转运蛋白稳定性、亚细胞定位和活性的重要手段。三 提出了具体的目标。在具体目标一中，我们将确定燕麦总酰化的性质。具体而言 目的II，我们将评估苏莫化在燕麦蛋白介导的药物在培养细胞转运中的作用。在……里面 具体目的III，我们将评估苏莫化在生理学和病理生理学上的相关性 燕麦介导的药物转运。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拟议的研究。了解 作为药物转运领域的一个新热点，苏莫化在燕麦调节中的作用将具有重要的意义 对未来旨在最大限度地提高治疗效果和最大限度地减少 毒性，并将使深入了解肾，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.