HIF-1α在小鼠胚胎神经系统发育中的表达及其RNAi的相关实验研究

发布时间：2019-02-25 18:46

【摘要】：神经系统是机体最重要和最复杂的系统,而其中神经管的发生是一个重要的涉及到建立中枢神经系统(central nervous system, CNS)原基的胚胎学事件,是指从神经板出现到神经管关闭的发育过程。在这个过程中,神经板必须准时准确地关闭形成神经管,神经系统才能得以正常发育;否则将出现神经管缺陷(neural tube defect, NTD),表现为各种脑和脊髓的发育畸形,如脊柱裂、露脑畸形等。露脑患儿均不能存活,脊柱裂患儿视情况而定,特别影响社会劳动力的是一些隐性脊柱裂患者,他们均给家庭和社会带来了严重的负担。为此,近一个多世纪以来,胚胎学家和发育神经生物学家坚持不懈地应用了许多不同的动物模型和不同的实验技术,试图探讨从神经板出现到神经管闭合这一涉及多因素调控的过程及机理,以避免和预防NTD 的发生,所以正常神经管形成的分子机制和NTD 的发病机理已成为当今神经科学研究的热点和前沿。神经管闭合后,神经管上皮细胞的进一步增生、分化和迁移对于神经系统正常形态和功能的建立十分重要。它的前端呈现三个膨大,依次称为前脑泡、中脑泡和菱脑泡,前脑泡发育为端脑和间脑,中脑泡发育为中脑,菱脑泡的前部发育为后脑,以后演变为脑桥和小脑,菱脑泡的后部发育为延髓,神经管尾端形成未来的脊髓。神经管发生和神经管关闭后的神经上皮细胞继续发育、分化和迁移,直至最终形成结构正常和功能完善的CNS,从基因水平而言,上述过程是一系列基因按照高度特异的时空模式表达并相互作用的结果。已知氧是保证各种生命活动最基本和最重要的因素,近年的研究证实人类胚胎、大鼠及小鼠胚胎发育中均存在低氧区,那么作为体内对低氧的重要调节因子——低氧诱导因子-1(hypoxia-inducible factor-1, HIF-1)是否参与其中呢?已有研究发现HIF-1α-/-小鼠显示有神经发育缺陷,包含神经管未闭和脑血管发育异常。但HIF-1α表达缺失是怎样影响神经管关闭的呢?确切的作用和分子机制又是什么呢?其在涉及NTD 发生的众多基因中是否处于调节者的地位呢?近年研究发现,有许多基因参与中枢神经系统发育的调控,外环境也是通过这些基因发挥作用的。作为参与体内对低氧调节的重要转录因子HIF-1,是否可能通过启动不同靶基因表达来参与神经管上皮细胞的增生、分化和迁移
[Abstract]:The nervous system is the most important and complex system in the body, and the occurrence of neural tubes is an important embryological event that involves the establishment of the (central nervous system, CNS) primordium of the central nervous system. It refers to the developmental process from the appearance of the nerve plate to the closure of the neural tube. In this process, the nerve plate must be closed on time and accurately to form the neural tube, so that the nervous system can develop normally. Otherwise, neural tube defect (neural tube defect, NTD),) will appear as various developmental malformation of brain and spinal cord, such as spina bifida, brain deformity and so on. None of the children with exposed brain can survive, and the children with spina bifida depend on the situation. It is some recessive spina bifida patients who especially affect the social labor force, and they all bring serious burden to the family and society. For more than a century, embryologists and developmental neurobiologists have persistently applied many different animal models and different experimental techniques. In order to avoid and prevent the occurrence of NTD, we tried to explore the process and mechanism of multi-factor regulation from the appearance of nerve plate to the closure of neural tube. Therefore, the molecular mechanism of normal neural tube formation and the pathogenesis of NTD have become the focus and frontier of neuroscience. After neural tube closure, the proliferation, differentiation and migration of neural tube epithelial cells are very important for the establishment of normal morphology and function of nervous system. Its front end presents three dilated brain bubbles, in turn called forebrain vesicles, midbrain vesicles and rhomboid vesicles. Forebrain vesicles develop into telencephalons and diencephalons, midbrain bubbles develop into mesencephalons, and the forepart of rhomboid vesicles develops into posterior brains, and then develops into pons and cerebellum. The posterior part of the rhombic vesicle develops into the medulla oblongata and the caudal end of the canal forms the future spinal cord. Neuroepithelial cells from neurogenesis and closure continue to develop, differentiate, and migrate until they eventually form a well-structured and well-functioning CNS, at the genetic level. These processes are the result of a series of genes expressed in a highly specific spatio-temporal pattern and interacting with each other. Oxygen is known to be the most basic and important factor to ensure all kinds of life activities. Recent studies have confirmed that hypoxia exists in the development of human embryos, rat embryos and mouse embryos. So is hypoxia-inducible factor-1 (hypoxia-inducible factor-1, HIF-1), an important regulator of hypoxia in vivo, involved in it? It has been found that HIF-1 伪-/-mice have neurodevelopmental defects, including neural canal patent and cerebral vascular dysplasia. But how does the lack of expression of HIF-1 伪 affect the closure of neural tubes? What are the exact roles and molecular mechanisms? Is it a regulator among the many genes involved in the occurrence of NTD? In recent years, it has been found that many genes are involved in the regulation of central nervous system development, and the external environment is also involved in the regulation of the development of the central nervous system. Whether HIF-1, an important transcription factor involved in the regulation of hypoxia in vivo, may participate in the proliferation, differentiation and migration of neural tube epithelial cells by initiating the expression of different target genes.
【学位授予单位】：第三军医大学
【学位级别】：硕士
【学位授予年份】：2005
【分类号】：R321

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