VESICLE TRANSPORT REGULATION IN INTOXICATION AND DISEASE

描述：(改编自《调查者摘要》)微囊藻毒素 水体中蓝藻产生的多肽肝毒素 包括便携式水供应，构成环境公共卫生 危险。冈田酸和相关化合物是引起 食用受污染的腹泻性贝类中毒 贝类。冈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2 A。即使是谦虚的 肝细胞中磷酸酶抑制的程度导致损害 微管依赖的转运、膜转运和受体介导 内吞作用，与增加磷酸化的几个组成部分 以微管为基础的运动蛋白、胞浆动力蛋白。我们的论点是，在 肝脏，动力蛋白复合体磷酸化的变化会导致 运动活动。这会转化为受损的膜运输，影响 基本的细胞/器官功能，如内吞和跨细胞作用。这个 这项建议的具体目标是：1)如何磷酸化 细胞质动力蛋白和相关多肽的调节？2)如何改变 胞浆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？产生这些影响的机制是什么？ 胞浆动力蛋白复合体的磷酸化和活性变化 导致内细胞膜流量改变？ 这些研究的完成将增加我们对基本肝功能的了解 以及对慢性低血压的长期后果提供洞察力 通过自来水或其他地方摄入这些毒素。 由于电机和/或MT变化而导致的膜交通中断，无论是 遗传或环境因素，都会导致肝功能受损和疾病。一个 更好地了解交通中涉及的组件的控制 在本申请中提出的将导致新的治疗策略在 发生毒物性或病理生理性肝损害事件。

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.