SEROTONIN SIGNALING SYSTEM IN S MANSONI

S MANSONI 中的血清素信号系统

• 批准号: 2060366
• 负责人: TAG E. MANSOUR
• 金额: $ 23.85万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-04-01 至 1996-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2060366
• 关键词: 6 phosphofructokinase; Schistosoma mansoni; Sf9 cell line; adenylate cyclase; antimony; biological signal transduction; complementary DNA; gene expression; glycolysis; guanine nucleotide binding protein; laboratory mouse; molecular cloning; mutant; northern blottings; nucleic acid sequence; protein kinase A; protein structure function; recombinant proteins; serotonin; serotonin receptor; southern blotting; western blottings

Schistosoma mansoni is a parasitic helminth that lives in the blood vessels of humans. It infects 220 million persons in 76 different countries including Puerto Rico and the Santa Lucia Islands, US territories. Although the parasite lives in the host in an aerobic millieu, it depends for its survival on anaerobic glycolysis. Our philosophy is that the better our understanding of the physiology and biochemistry of the parasite, the better our chance of identifying unique targets that can be selectively influenced by prospective chemotherapeutic agents. In order to survive, S. mansoni must metabolize every 6 hours an amount of glucose equivalent to its dry weight. Inhibition of a rate limiting enzyme in glycolysis, such as phosphofructokinase, by chemotherapeutic agents (e.g., organic antimonial) is lethal to the parasites. This research focuses on a hormonal/transduction system discovered in our laboratory in S. mansoni and other trematodes that regulates glycolysis in these parasites. Serotonin is a hormone-like agent in S. mansoni. It stimulates glycolysis and glycogenolysis and activates adenylate cyclase, glycogen phosphorylase and phosphofructokinase. It has many of the same functions that epinephrine has in mammals. The transmembrane signalling system for serotonin is composed of serotonin receptors that are unique to the parasite; a GTP binding protein; adenylate cyclase, a c-AMP-dependent protein kinase and signal and target proteins(e.g., phosphofructokinase). In this proposal we plan to study in depth three components of the serotonin signalling system: phosphofructokinase, GTP binding proteins, and serotonin receptors. Since our first attempt to renew this grant, we have succeeded in cloning two components of the signalling system, the Gsa protein and phosphofructokinase. We will complete the structural and functional analysis of the Gsa clone. We will express the PFK gene in bacterial or insect cells and study the biochemical nature of the recombinant protein. We plan to continue our work on cloning the serotonin receptor from the parasites and on characterizing its molecular and biochemical properties. Our studies have more significance than their possible use for drug development. Characterization of the molecular components of this "primitive" signalling system contribute to our basic knowledge of transmembrane signal transduction.

曼氏菌是一种寄生的蠕虫，活在血液中 人类的船只。 它感染了76种不同的人口2.2亿人 包括波多黎各和美国圣卢西亚群岛在内的国家 领土。 尽管寄生虫生活在有氧运动中 Millieu，这取决于其生存在厌氧糖酵解上。 我们的 哲学是，我们对生理学和 寄生虫的生物化学，我们确定独特的机会越好 可以选择性地影响潜在的目标 化学治疗剂。 为了生存，曼氏链球菌必须代谢 每6小时，一定数量的葡萄糖等效于其干重。 在糖酵解中抑制限制酶的速率，例如 化学治疗剂（例如，有机） 抗微虫具有致命的寄生虫。 这项研究重点是 在我们的S. Mansoni实验室中发现的激素/转导系统 以及调节这些寄生虫糖酵解的其他爆发。 5-羟色胺是S. Mansoni中的激素样剂。 它刺激 糖酵解和糖原分解并激活腺苷酸环化酶，糖原 磷酸化酶和磷酸果糖激酶。 它具有许多相同的功能 肾上腺素在哺乳动物中具有。 用于的跨膜信号系统 5-羟色胺由5-羟色胺受体组成，这些受体是独有的 寄生虫； GTP结合蛋白；腺苷酸环化酶，依赖于CAMP 蛋白激酶以及信号和靶蛋白（例如磷酸果酶动物酶）。 在此提案中，我们计划深入研究 5-羟色胺信号系统：磷酸果糖激酶，GTP结合蛋白， 和5-羟色胺受体。 自从我们第一次尝试续签这笔赠款以来， 我们成功地克隆了信号系统的两个组件，即 GSA蛋白和磷酸果糖激酶。 我们将完成结构和 GSA克隆的功能分析。 我们将在 细菌或昆虫细胞并研究 重组蛋白。 我们计划继续我们的克隆 寄生虫的5-羟色胺受体并表征其分子 和生化特性。 我们的研究比 它们可能用于药物开发。 表征 该“原始”信号系统的分子成分有助于 我们对跨膜信号转导的基本知识。