p300及其结合功能在缺氧神经细胞损伤中的作用

发布时间：2018-06-27 13:54

本文选题：p300 + p65　；参考：《第三军医大学》2005年博士论文

【摘要】：缺氧是许多疾病所共有的一个基本病理过程。是临床医学、高原医学、航空航天医学等研究的核心问题。研究缺氧发生和发展的规律以及缺氧习服机制，对于保障高原建设者和世居高原人群的健康、边疆地区的经济发展、巩固国防以及拓宽人类生存空间具有重要的现实意义。脑是机体内各系统缺氧反应的主宰者，只有在脑组织功能正常的情况下，才有可能通过呼吸、循环、血液等系统建立起一整套适应缺氧环境的代偿机制，因此，缺氧中枢神经系统功能障碍及习服的分子机制是高原医学研究的首要问题之一。基因差异表达是调控细胞生命活动的核心机制，是生物体完成基本生命活动以及对外界刺激作出应答的分子基础。阐明基因选择性表达所依赖的调控信息及其相互作用的分子机制，已经成为功能基因组学领域内基因表达调控研究国际竞争的焦点。对低氧应激反应相关基因表达及调控信息的认识成为研究缺氧中枢神经系统功能障碍及习服的核心内容之一。人类基因组系统分析的结果告诉我们，在序列占有量还不到整个基因组2％的蛋白质组中，调节基因表达的转录因子占据了相当大的比例，约3000左右。这些转录因子在调控基因表达时相互作用，，形成了极为复杂的基因表达调控网络。从研究单一的调控环节拓展到深入探讨它们之间的相互联系及其控制过程，从调控网络的角度探寻低氧适应基因及其诱导的调控机制，不仅有助于更深入认识低氧适应的分子机制，而且可为有效预防高原低氧损伤医学措施的制定提供更直接的科学依据。近十年的研究证实，在基因表达调控网络中，除了转录因子这一活跃的因素以外，转录辅激活子因其多转录因子结合功能，而成为网络中活跃的因素之一。转录辅激活子表达变化及其结合蛋白谱的改变成为联系外界信号和基因表达的中心环节。转录辅激活子p300在缺氧基因表达调控中起重要作用，已发现多种缺氧相关转录因子活性的发挥依赖p300，p300的蛋白结合功能受外界环境、细胞环境的精密调控。我们推测p300蛋白表达量、蛋白结合功能是影响缺氧相关基因的选择性表达的重要方面。而相关的研究尚未见报导。本研究以大鼠海马组织及NPC12细胞为研究对象，探讨p300表达及其结合功能在缺氧神经细胞损伤中的作用。课题分为四个部分：一、比较大鼠p300蛋白表达的细
[Abstract]:Hypoxia is a basic pathological process common to many diseases. It is the core problem of clinical medicine, plateau medicine, aerospace medicine and so on. It is of great practical significance to study the regularity of the occurrence and development of hypoxia and the mechanism of acclimatization of hypoxia to ensure the health of plateau builders and people living on the plateau, the economic development of frontier areas, the consolidation of national defense and the expansion of human living space. The brain is the master of anoxic reaction in various systems of the body. Only when the function of brain tissue is normal can it be possible to establish a complete set of compensatory mechanisms adapted to hypoxia environment through the systems of respiration, circulation, blood and so on. The molecular mechanism of anoxic central nervous system dysfunction and acclimatization is one of the most important problems in plateau medicine. Gene differential expression is the core mechanism of regulating cell life activity and the molecular basis for organism to complete basic life activities and respond to external stimuli. It has become the focus of international competition in the field of functional genomics to elucidate the regulatory information and the molecular mechanism of the interaction between selective gene expression and gene expression. The recognition of gene expression and regulation information related to hypoxia stress response has become one of the core contents in the study of hypoxic central nervous system dysfunction and acclimatization. The results of systematic analysis of human genome tell us that in the proteome with less than 2% of the total genome, transcription factors that regulate gene expression occupy a large proportion, about 3000. These transcription factors interact with each other in the regulation of gene expression and form an extremely complex regulatory network of gene expression. From the study of a single regulatory link to the in-depth study of their interrelation and their control process, and from the perspective of regulatory networks, we explore the hypoxic adaptation gene and its induced regulatory mechanism. It can not only help to understand the molecular mechanism of hypoxia adaptation, but also provide a more direct scientific basis for the development of medical measures to prevent hypoxic injury at high altitude. In recent ten years, it has been proved that in gene expression regulation network, transcription coactivator is one of the active factors in the network because of its multi-transcription factor binding function, in addition to the active factor of transcription factor, transcriptional coactivator has become one of the active factors in the network because of its multiple transcriptional factor binding function. The changes of transcriptional coactivator expression and its binding protein profile have become the central link between external signals and gene expression. Transcription coactivator p300 plays an important role in the regulation of hypoxia gene expression. It has been found that the activities of various hypoxia related transcription factors play a role in the p300 protein binding function and are precisely regulated by the external environment and cell environment. We speculate that p300 protein expression and protein binding function are important factors affecting the selective expression of hypoxia related genes. The relevant studies have not been reported. The purpose of this study was to investigate the role of p300 expression and its binding function in hypoxic nerve cell injury in rat hippocampal tissue and NPC12 cells. The task is divided into four parts: first, compare the expression of p300 protein in rats
【学位授予单位】：第三军医大学
【学位级别】：博士
【学位授予年份】：2005
【分类号】：R363

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