Screening And Functional Study Of Brain Aging Related Orthologous Genes Between Human And Mice In The Frontal Cortex Of SAMP8

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.