早衰小鼠P8（SAMP8）额叶脑衰老相关人鼠同源基因筛选及功能研究
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摘要
随着世界各国人口老龄化进程的到来,研究衰老的机制,进一步防治衰老相关的疾病已逐渐成为当今医学科学研究新的热点。为了更深入地进行脑衰老及相关疾病发生发展分子机制的研究,我们利用目前公认的脑衰老哺乳动物模型——SAMP8(senescence-accelerated mice prone 8,快速老化小鼠-8)——作为研究对象,利用微点阵技术(Microarray/Gene Chip/基因芯片),对12月龄与4月龄SAMP8鼠额叶基因的转录水平进行了对比研究。
Microarray是将指大量寡核苷酸分子固定于支持物上,然后与标记的样品进行杂交,通过检测杂交信号的强弱进而判断样品中靶分子数量的一项新兴生物技术。1995年,Stanford大学的P Brown实验室发明了第一块以玻璃为载体的基因微点阵芯片,标志着基因芯片技术进入了广泛研究和应用的时期。基因芯片被广泛应用于高通量基因表达水平检测、基因诊断、药物筛选及个性化给药、新基因发现等领域,成为21世纪生物技术发展的重要特征。
生物信息学(Bioinformatics)是20世纪80年代末随着人类基因组计划(human genome project,HGP)的启动而兴起的一门新的边缘学科和技术,是分子生物学与计算机科学的交叉。其任务之一为发展有效的信息分析工具,构建适合于基因组研究的数据库,搜集、管理和使用人类基因组和模式生物基因组的巨量信息。迄今已发展完善了GenBank核酸序列、SWISS-PROT蛋白质序列和PDB生物大分子结构等著名的数据库,开发了如Blast、NEBcutter、Primer-3等上百种生物信息分析软件。生物信息学就如同一个向导,为科研工作者提供了一个崭新的工具,帮助科研人员从纷繁复杂生物信息中找寻真理。
同源基因通常指不同物种中起源于同一祖先的基因,在遗传学中,同源这一概念主要是指序列同源。直向同源序列(Orthologs)被认为在不同的物种中具有相近甚至相同的功能、相似的调控途径,扮演相似甚至相同的角色,而且,绝大多数核心生物功能就是由相当数量的直向同源基因所承担。因此,研究模式生物中与人同源基因的功能对揭示人体各种生理过程及疾病发生发展分子机制具有重要意义。
本研究应用基因芯片技术检测12月龄和4月龄SAMP8鼠额叶基因表达谱,筛选到65个明显上调基因和632个明显下调基因。上调基因多为促炎症、应激反应相关基因;而下调基因则多为突触可塑性、囊泡运输、线粒体功能、蛋白质和DNA修复、神经激素等相关基因。进一步经生物信息学分析及RT-PCR、WesternBlot验证,证实了4个基因——Gnaq(Guanine Nucleotide Binding Protein-alpha qPolypeptide)、KIF1b(Kinesin Family Member 1b)、Sort1(sortilin-1)、Sst(somatostatin)——是脑衰老相关人鼠同源基因。这4个基因随衰老呈明显降低的mRNA转录水平和蛋白表达水平。这些发现将有助于更好地在模型动物中研究脑衰老及相关疾病发生的分子机制。
基于上述发现,我们进一步研究抗脑衰老药物对脑衰老相关人鼠同源基因表达的影响及这些基因在脑衰老过程中的功能。首先我们研究了天麻素对SAMP8鼠Sst表达水平及相关衰老表征的影响。结果显示天麻素能明显上调SAMP8鼠额叶内Sst的转录水平和蛋白表达水平,并明显改善SAMP8鼠的学习记忆能力和其它衰老相关表征。这些结果提示天麻素治疗可能通过增进额叶Sst的转录和表达水平以延缓SAMP8鼠的脑衰老进程,各种原因所致的Sst表达水平降低可能是导致脑衰老及相关疾病的分子机制之一。Gnaq、KIF1b及Sort1的功能研究正在进行之中。
Due to the increasing amount of aged people in the world's population, it is becoming a new focus to study mechanisms of aging and to prevent and treat aging-related diseases. In order to illuminate the underlying molecular mechanisms of brain aging and concerned diseases, we exploited the received mammal brain aging model, senescence-accelerated mice prone 8 (SAMP8), as a researched object. The transcriptional level of genes in the frontal cortex of 12-month SAMP8 and 4-month SAMP8 was determined by microarray.
Microarray, also known as gene chip, is a new biotechnique which can determine high density of hybridization signal by pre-fixing huge amount of oligonucleotide molecules on a supporter chip. In 1995, the P Browm Lab of Stanford University created the first glass-slide-supported gene microarray chip. From then, microarray was extensively used in gene expression spectrum, gene diagnosis, drug screening, individual administration and new gene discovering. The general use of microarray has become a great characteristic of biotechnology in 21 century.
Bioinformatics is also a new subject and technique developed with the initiation of Human Genome Project (HGP) in the late 1980s. It is a combination between biology and computer. One of Bioinformatics' tasks is to help researchers collecting, managing, using the giant information of human genome and model animals' genomes by developing efficient bioinformation analyzing tools and by establishing databases adapt to genome research. So far, some famous databases have been built up and exploited extensively, such as GenBank nucleotide sequense database, SWISS-PROT protein sequence database and PDB biomacromolecule structure database. And lots of useful softwares such as Blast, NEBcutter and Primer- 3 also have been developed. Bioinformatics is just like a guider directing researchers to find truth from mass of bioinformation.
Genes contained in different species but evolved from the same ancestor were defined as orthologous genes. In genetics, orthologous generally mean similar sequence. Orthologous genes in variant species usually perform similar functions, exploit same regulatory pathways and play equal roles. Furthermore, most of the key biological functions are controlled by orthologous genes. Therefore, exploring the functions of othologous genes in animal model can provide significant clues in revealing underlying molecular mechanisms of variant physiologic and pathologic processes in human body.
In the present study, Microarray technology was employed to profile the differentially expressed genes between 12 and 4 month-old frontal cortex of the SAMP8 model. 65 up-regulated genes as well as 632 down-regulated genes were identified. Most of the up-regulated genes are related to inflammations and stress responses, but large part of the down-regulated genes play roles in synapse plasticity, vesicular transportation, mitochondria function, protein and DNA repair, and neurohormone secreting. By further analysis with bioinformatics and verification with RT-PCR and Western Blot, we demonstrated that four genes: Gnaq (Guanine Nucleotide Binding Protein-alpha q Polypeptide)、KIF1b (Kinesin Family Member 1b)、Sort1 (sortilin-1)、Sst (somatostatin), are brain aging related orthologous genes between human and mice. These 4 orthologous genes show reduced mRNA transcription and protein expression level with aging. These finds would contribute to exploring the molecular mechanisms of brain aging and associated diseases.
Based on the above discovery, we explored the underlying mechanisms of the 4 orthologous genes in brain aging process. In the first, we explored the effect of Gastrodin treatment on the memory, learning, aging related symbols of SAMP8 and the expression level of Sst in the frontal cortex. Our data indicated that administration of Gastrodin can significantly up-regulate the mRNA and protein level of Sst in the frontal cortex, as well significantly promote the learning and memory ability and postpone the emergence of aging related phenotype of SAMP8. These results implied that Gastrodin may prevent the onset of brain aging and brain-aging-related diseases probably by promoting expression level of Sst in the frontal cortex. Reduced Sst expression caused by variant factors may be one of the mechanisms leading to brain aging and related diseases. The exploration of other orthologous genes (Gnaq, KIF1b and Sort1) is being performed.
Microarray是将指大量寡核苷酸分子固定于支持物上,然后与标记的样品进行杂交,通过检测杂交信号的强弱进而判断样品中靶分子数量的一项新兴生物技术。1995年,Stanford大学的P Brown实验室发明了第一块以玻璃为载体的基因微点阵芯片,标志着基因芯片技术进入了广泛研究和应用的时期。基因芯片被广泛应用于高通量基因表达水平检测、基因诊断、药物筛选及个性化给药、新基因发现等领域,成为21世纪生物技术发展的重要特征。
生物信息学(Bioinformatics)是20世纪80年代末随着人类基因组计划(human genome project,HGP)的启动而兴起的一门新的边缘学科和技术,是分子生物学与计算机科学的交叉。其任务之一为发展有效的信息分析工具,构建适合于基因组研究的数据库,搜集、管理和使用人类基因组和模式生物基因组的巨量信息。迄今已发展完善了GenBank核酸序列、SWISS-PROT蛋白质序列和PDB生物大分子结构等著名的数据库,开发了如Blast、NEBcutter、Primer-3等上百种生物信息分析软件。生物信息学就如同一个向导,为科研工作者提供了一个崭新的工具,帮助科研人员从纷繁复杂生物信息中找寻真理。
同源基因通常指不同物种中起源于同一祖先的基因,在遗传学中,同源这一概念主要是指序列同源。直向同源序列(Orthologs)被认为在不同的物种中具有相近甚至相同的功能、相似的调控途径,扮演相似甚至相同的角色,而且,绝大多数核心生物功能就是由相当数量的直向同源基因所承担。因此,研究模式生物中与人同源基因的功能对揭示人体各种生理过程及疾病发生发展分子机制具有重要意义。
本研究应用基因芯片技术检测12月龄和4月龄SAMP8鼠额叶基因表达谱,筛选到65个明显上调基因和632个明显下调基因。上调基因多为促炎症、应激反应相关基因;而下调基因则多为突触可塑性、囊泡运输、线粒体功能、蛋白质和DNA修复、神经激素等相关基因。进一步经生物信息学分析及RT-PCR、WesternBlot验证,证实了4个基因——Gnaq(Guanine Nucleotide Binding Protein-alpha qPolypeptide)、KIF1b(Kinesin Family Member 1b)、Sort1(sortilin-1)、Sst(somatostatin)——是脑衰老相关人鼠同源基因。这4个基因随衰老呈明显降低的mRNA转录水平和蛋白表达水平。这些发现将有助于更好地在模型动物中研究脑衰老及相关疾病发生的分子机制。
基于上述发现,我们进一步研究抗脑衰老药物对脑衰老相关人鼠同源基因表达的影响及这些基因在脑衰老过程中的功能。首先我们研究了天麻素对SAMP8鼠Sst表达水平及相关衰老表征的影响。结果显示天麻素能明显上调SAMP8鼠额叶内Sst的转录水平和蛋白表达水平,并明显改善SAMP8鼠的学习记忆能力和其它衰老相关表征。这些结果提示天麻素治疗可能通过增进额叶Sst的转录和表达水平以延缓SAMP8鼠的脑衰老进程,各种原因所致的Sst表达水平降低可能是导致脑衰老及相关疾病的分子机制之一。Gnaq、KIF1b及Sort1的功能研究正在进行之中。
Due to the increasing amount of aged people in the world's population, it is becoming a new focus to study mechanisms of aging and to prevent and treat aging-related diseases. In order to illuminate the underlying molecular mechanisms of brain aging and concerned diseases, we exploited the received mammal brain aging model, senescence-accelerated mice prone 8 (SAMP8), as a researched object. The transcriptional level of genes in the frontal cortex of 12-month SAMP8 and 4-month SAMP8 was determined by microarray.
Microarray, also known as gene chip, is a new biotechnique which can determine high density of hybridization signal by pre-fixing huge amount of oligonucleotide molecules on a supporter chip. In 1995, the P Browm Lab of Stanford University created the first glass-slide-supported gene microarray chip. From then, microarray was extensively used in gene expression spectrum, gene diagnosis, drug screening, individual administration and new gene discovering. The general use of microarray has become a great characteristic of biotechnology in 21 century.
Bioinformatics is also a new subject and technique developed with the initiation of Human Genome Project (HGP) in the late 1980s. It is a combination between biology and computer. One of Bioinformatics' tasks is to help researchers collecting, managing, using the giant information of human genome and model animals' genomes by developing efficient bioinformation analyzing tools and by establishing databases adapt to genome research. So far, some famous databases have been built up and exploited extensively, such as GenBank nucleotide sequense database, SWISS-PROT protein sequence database and PDB biomacromolecule structure database. And lots of useful softwares such as Blast, NEBcutter and Primer- 3 also have been developed. Bioinformatics is just like a guider directing researchers to find truth from mass of bioinformation.
Genes contained in different species but evolved from the same ancestor were defined as orthologous genes. In genetics, orthologous generally mean similar sequence. Orthologous genes in variant species usually perform similar functions, exploit same regulatory pathways and play equal roles. Furthermore, most of the key biological functions are controlled by orthologous genes. Therefore, exploring the functions of othologous genes in animal model can provide significant clues in revealing underlying molecular mechanisms of variant physiologic and pathologic processes in human body.
In the present study, Microarray technology was employed to profile the differentially expressed genes between 12 and 4 month-old frontal cortex of the SAMP8 model. 65 up-regulated genes as well as 632 down-regulated genes were identified. Most of the up-regulated genes are related to inflammations and stress responses, but large part of the down-regulated genes play roles in synapse plasticity, vesicular transportation, mitochondria function, protein and DNA repair, and neurohormone secreting. By further analysis with bioinformatics and verification with RT-PCR and Western Blot, we demonstrated that four genes: Gnaq (Guanine Nucleotide Binding Protein-alpha q Polypeptide)、KIF1b (Kinesin Family Member 1b)、Sort1 (sortilin-1)、Sst (somatostatin), are brain aging related orthologous genes between human and mice. These 4 orthologous genes show reduced mRNA transcription and protein expression level with aging. These finds would contribute to exploring the molecular mechanisms of brain aging and associated diseases.
Based on the above discovery, we explored the underlying mechanisms of the 4 orthologous genes in brain aging process. In the first, we explored the effect of Gastrodin treatment on the memory, learning, aging related symbols of SAMP8 and the expression level of Sst in the frontal cortex. Our data indicated that administration of Gastrodin can significantly up-regulate the mRNA and protein level of Sst in the frontal cortex, as well significantly promote the learning and memory ability and postpone the emergence of aging related phenotype of SAMP8. These results implied that Gastrodin may prevent the onset of brain aging and brain-aging-related diseases probably by promoting expression level of Sst in the frontal cortex. Reduced Sst expression caused by variant factors may be one of the mechanisms leading to brain aging and related diseases. The exploration of other orthologous genes (Gnaq, KIF1b and Sort1) is being performed.
引文
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