Deciphering the Evolution of the Opioid/Orphanin Gene Family

破译阿片类药物/孤啡肽基因家族的进化

• 批准号: 0132210
• 负责人: Robert Dores
• 金额: $ 24万
• 依托单位: University of Denver
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-15 至 2006-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0132210&HistoricalAwards=false
• 关键词: Deciphering; Evolution; Opioid; Orphanin; Gene

A striking feature of chemical communication systems in the brains of jawed vertebrates (gnathostomes) is the apparent duplication of genes that produce useful neuropeptide compounds. For example, in mammals there are four neuropeptide precursors (proenkephalin, prodynorphin, proopiomelanocortin, and proorphanin) that produce opiate-like peptides (opioids) or nociceptic-like peptides (orphanins). These four precursors are members of a gene family, the opioid/orphanin family, and the apparent redundancy of genes in this family in fact reflects the evolutionary history of the vertebrates. Gene duplication events at discrete points in vertebrate evolution have allowed for the layering of neuropeptide networks over time, and have led to a diversification in function of these peptide products, including roles in analgesia, nociception, motor control, and feeding. This project combines molecular biology procedures with a comparative approach to define trends in the evolutionary radiation of the orphanin/opioid gene family in gnathostomes. The cloning and sequencing of cDNAs, coupled with the measurement of gene expression by real-time PCR, will generate a database of sequences for each gene in the family that will be used to perform cladistic analyses and to identify novel opioid sequences. By examining selected vertebrate lineages where the evolution of this gene family has been slower than in mammals or teleost fish, it is possible to make inferences about the origin and transitions in the sequential evolution of this gene family. These data will test the 'proenkephalin hypothesis' that the ancestral gene in the opioid/orphanin gene family was a gene that coded for the enkephalin-like product. Results will provide a new level of understanding of the evolutionary mechanisms underlying the functional diversity in this important family of neuropeptides. The impact of this project will extend beyond neuroendocrinology to molecular neurobiology in general, and to evolutionary biology with respect to the trends that promote species diversity. Multi-disciplinary undergraduate and graduate training also is an important component of this project.

有颌脊椎动物（颌口动物）大脑中化学通讯系统的一个显着特征是产生有用神经肽化合物的基因明显重复。 例如，在哺乳动物中，有四种神经肽前体（脑啡肽原、强啡肽原、阿片黑皮素原和孤啡肽原）可产生阿片样肽（阿片类药物）或伤害性类肽（孤啡肽）。 这四个前体是阿片类/孤啡肽基因家族的成员，该家族中基因的明显冗余实际上反映了脊椎动物的进化历史。 脊椎动物进化中离散点的基因复制事件使得神经肽网络随着时间的推移而分层，并导致这些肽产品的功能多样化，包括在镇痛、伤害感受、运动控制和进食中的作用。 该项目将分子生物学程序与比较方法相结合，以确定颌口动物孤啡肽/阿片类药物基因家族的进化辐射趋势。 cDNA 的克隆和测序，再加上通过实时 PCR 测量基因表达，将为家族中每个基因生成一个序列数据库，该数据库将用于进行分支分析并鉴定新的阿片类药物序列。 通过检查该基因家族的进化比哺乳动物或硬骨鱼慢的选定脊椎动物谱系，可以推断该基因家族连续进化的起源和转变。 这些数据将检验“脑啡肽原假说”，即阿片类药物/孤啡肽基因家族中的祖先基因是编码脑啡肽样产物的基因。 结果将为这个重要的神经肽家族功能多样性的进化机制提供新的理解。 该项目的影响将超越神经内分泌学，扩展到一般的分子神经生物学，以及关于促进物种多样性趋势的进化生物学。 多学科本科生和研究生培养也是该项目的重要组成部分。