Co-evolution of the Opioid/Orphanin Gene Family and Cognate Receptor Gene Families

阿片类药物/孤啡肽基因家族和同源受体基因家族的共同进化

• 批准号: 0516958
• 负责人: Robert Dores
• 金额: $ 29万
• 依托单位: University of Denver
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0516958&HistoricalAwards=false
• 关键词: Co; evolution; Opioid; Orphanin; Gene

Title:Co-evolution of the Opioid/Orphanin Gene Family and Cognate Receptor Gene Families. PI: Robert M. Dores. Institution : University of Denver Communication among organ systems is accomplished by two intercellular communication systems, the nervous system and the endocrine system, that facilitates the flow of information throughout the body. In these communication networks, critical messages are carried by chemical signals (ligands) that interact in a highly selective manner with specific receptors on a target cell, a "lock and key" strategy. The origin of these ligand/receptor interactions are unknown, but the studies in this proposal will examine species from old lineages in order to reconstruct the transformations that have occurred in ligand-coding and receptor-coding genes during the evolution of distinct chemical communication networks. In order to study the co-evolution of ligand-coding genes and their corresponding receptor-coding genes this proposal will use the opioid/orphanin ligand-coding gene family (the source of opioid and melanocortin ligands), the opioid receptor-coding gene family and the melanocortin receptor gene family, which provide excellent models. The opioid/orphanin ligands influence analgesia, cardiovascular function, and some actions of the immune system, while the melanocortins are involved in chronic stress regulation, fat and glucose metabolism, and feeding behavior. Students will analyze species at critical branch points in the radiation of vertebrates such as: the lungfish, Neoceratodus forsteri, the white sturgeon, Acipenser transmontanus, the horn shark, Heterodontus francisci , the ratfish, Hydrolagus colliei, and the jawless vertebrates, Myxine glutinosa (hagfish) and Petromyzon marinus (lamprey). Studies will integrate the cloning of ligand coding genes with the cloning of their respective cognate receptor-coding genes in these species. The cloned receptors will be expressed in cell lines for binding study analysis, and the distribution of these receptors in the central nervous system and in peripheral tissues will be determined. These studies will reveal novel sequences for both ligands and receptors in the species that have been selected for these projects. Receptor sequence and ligand sequence databases will be created to identify amino acid motifs that could be modified in future site directed mutagenesis experiments to address structure/function related questions. These studies may lead to the development of analogs to the ligands (opioids and melanocortins) that may have therapeutic applications. Projects will be conducted by Ph.D. and MS graduate students and undergraduate honors students. Minority students will be recruited for summer REU (NSF Research Experience for Undergraduates) positions. Finally, a molecular cloning project related to this set of studies will be incorporated into the lab techniques course, BIOL 3655 "Molecular Neuroendocrinology" annually. This proposal fits into the area of Biological Systems Informatics in which questions of genome evolution can be addressed using genomic sequence database analyses. This proposal will both add information to a large ligand/receptor sequence database, as well as "data-mine" the database for new insights into receptor/ligand protein evolution and linked gene co-evolution.

阿片/孤儿基因家族和同源受体基因家族的共同进化。派：罗伯特·M·多雷斯。机构：丹佛大学器官系统间的通讯由神经系统和内分泌系统两个细胞间通讯系统完成，这两个系统促进了信息在全身的流动。在这些通信网络中，关键信息由化学信号(配体)携带，这些信号以高度选择性的方式与目标细胞上的特定受体相互作用，这是一种“锁和钥匙”策略。这些配体/受体相互作用的起源尚不清楚，但本建议中的研究将检查来自古老谱系的物种，以重建在不同的化学通信网络进化过程中发生在配体编码和受体编码基因中的转换。为了研究配体编码基因及其相应的受体编码基因的共同进化，本提议将使用阿片/孤儿配体编码基因家族(阿片和黑素皮质素配体的来源)、阿片受体编码基因家族和黑素皮质素受体基因家族，这三个基因家族提供了很好的模型。阿片/孤儿配体影响镇痛、心血管功能和免疫系统的一些活动，而黑素皮质素参与慢性应激调节、脂肪和葡萄糖代谢以及摄食行为。学生将分析脊椎动物辐射的关键分支点上的物种，如肺鱼、新角鱼、白鲟鱼、大西洋鲟鱼、角鲨、异齿鲨、鼠鱼、水豚、无颌脊椎动物粘液鱼和七鳃鳗。研究将把克隆配体编码基因与克隆它们各自在这些物种中的同源受体编码基因结合起来。克隆的受体将在细胞系中表达，用于结合研究，并将确定这些受体在中枢神经系统和周围组织中的分布。这些研究将揭示为这些项目选择的物种的配体和受体的新序列。将建立受体序列和配体序列数据库，以确定在未来的定点突变实验中可以修改的氨基酸基序，以解决结构/功能相关的问题。这些研究可能导致开发可能具有治疗应用的配体(阿片类药物和黑素皮质素)的类似物。项目将由博士、硕士研究生和本科生荣誉学生进行。少数族裔学生将被招募到暑期REU(NSF本科生研究经验)职位。最后，与这一系列研究相关的分子克隆项目将被纳入实验室技术课程，每年的Biol 3655“分子神经内分泌学”。这一建议适用于生物系统信息学领域，在该领域中，基因组进化的问题可以通过基因组序列数据库分析来解决。这一建议将为一个庞大的配体/受体序列数据库增加信息，并对数据库进行数据挖掘，以获得对受体/配体蛋白质进化和相关基因共同进化的新见解。