VESICLE TRANSPORT REGULATION IN INTOXICATION AND DISEASE

中毒和疾病中的囊泡运输调节

• 批准号: 2883905
• 负责人: MARIA T RUNNEGAR
• 金额: $ 25.45万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2883905
• 关键词: biological transport; dynein ATPase; enzyme inhibitors; hepatotoxin; immunoprecipitation; liver toxic disorder; microtubules; okadaic acid; pathologic process; phosphatase inhibitor; phosphorylation; protein kinase; seafood poisoning; vesicle /vacuole; video microscopy

DESCRIPTION: (Adapted from the Investigator's Abstract) Microcystins are Peptide hepatotoxins produced by cyanobacteria present in water bodies including portable water supplies, constituting an environmental public health hazard. Okadaic acid and related compounds are the toxic components causing diarrheic shellfish poisoning through the consumption of contaminated shellfish. The mode of action of okadaic acid and microcystins is the potent, specific inhibition of the ser/thr protein phosphatases 1 and 2A. Even a modest degree of phosphatase inhibition in hepatocytes results in impaired microtubule-dependent transport, membrane trafficking, and receptor-mediated endocytosis, with increased phosphorylation of several components of the microtubule-based motor protein, cytoplasmic dynein. Our thesis is that in liver, changes in the phosphorylation of the dynein complex cause changes in motor activity. This translates into impaired membrane trafficking, affecting essential cellular/organ functions like endocytosis and transcytosis. The specific aims of this proposal are: 1) How is the phosphorylation of cytoplasmic dynein and associated polypeptides regulated? 2) How do changes in phosphorylation of cytoplasmic dynein and associated proteins contribute to changes in dynein activity ? What is the mechanism for these effects? 3) Do changes in the phosphorylation and activity of the cytoplasmic dynein complex lead to altered endocytic membrane traffic? Completion of these studies will increase our knowledge of basic liver function as well as provide insights into the long term consequences for chronic low dose ingestion of these toxins through the water supply or elsewhere. Disruption of membrane traffic because of motor and/or MT changes, be they genetic or environmental, will cause impaired hepatic function and disease. A better knowledge of the control of the components involved in traffic as proposed in this application will lead to novel therapeutic strategies in the event of toxicological or pathophysiological liver damage.

描述：（改编自研究者摘要）微囊藻毒素是 水体中蓝藻产生的肽肝毒素 包括便携式供水，构成环境公共卫生 冒险。冈田酸和相关化合物是导致 因食用受污染的贝类而引起腹泻性贝类中毒 贝类。大田酸和微囊藻毒素的作用方式是有效的， 特异性抑制丝氨酸/苏氨酸蛋白磷酸酶 1 和 2A。即使是一个谦虚的人 肝细胞磷酸酶抑制程度导致肝细胞功能受损 微管依赖性运输、膜运输和受体介导 内吞作用，增加了几种成分的磷酸化 基于微管的运动蛋白，细胞质动力蛋白。我们的论点是，在 肝脏中，动力蛋白复合物磷酸化的变化会导致 运动活动。这会导致膜运输受损，影响 重要的细胞/器官功能，如胞吞作用和转胞吞作用。这 该提案的具体目标是：1）如何磷酸化 细胞质动力蛋白和相关多肽受到调节吗？ 2）如何改变 细胞质动力蛋白和相关蛋白的磷酸化有助于 动力蛋白活性的变化 ?这些效应的机制是什么？ 3）做 细胞质动力蛋白复合物磷酸化和活性的变化 导致内吞膜运输改变？ 完成这些研究将增加我们对基本肝功能的了解 并提供对慢性低血压的长期后果的见解 通过供水或其他地方剂量摄入这些毒素。 由于电机和/或 MT 变化而导致膜流量中断，无论是 遗传或环境因素，都会引起肝功能受损和疾病。一个 更好地了解交通中涉及的组件的控制 本申请中提出的将导致新的治疗策略 发生毒理学或病理生理性肝损伤。