过量亚硝酸盐暴露和内源性视黄酸信号不足影响斑马鱼胚胎心脏瓣膜发生

发布时间：2022-01-20 16:00

　　瓣膜通常位于心脏的流出道和房室通道处,在心脏内部起着防止血液倒流的作用。由于瓣膜结构的复杂性和生成时间的长期性使得瓣膜发生很容易受到致畸因子的影响,因此先天性瓣膜疾病在成活出生婴儿中发病比例很高。但目前只有20%左右的先心病可以诊断出确切的病因。因此,研究环境因子和遗传因素在瓣膜发生过程中的作用对防治新生儿先天性心脏发育缺陷有重要的意义。亚硝酸盐是一种常用的食品添加剂,除大量存在在环境中外,亦广泛分布于我们身体的多种组织和器官中。通过参与体内的硝酸盐-亚硝酸盐-一氧化氮稳态发挥着重要的生物和生理学作用。已知过量的亚硝酸盐可对人类健康产生导致多种毒理作用,但其对脊椎动物的心脏瓣膜发生的影响迄今尚未见报道,在本研究中,我们利用了在研究心血管系统发育方面具有独特优势的模式动物斑马鱼,探讨了亚硝酸盐在脊椎动物早期胚胎发生过程中对瓣膜发育的影响。通过将斑马鱼胚胎曝露在亚硝酸盐的环境中生长,我们的研究发现亚硝酸盐会以浓度依赖的方式致脊椎动物胚胎心脏出现心脏水肿等发育异常,其作用的时间窗自36 hpf（受精后36小时）起。对24hpf至48hpf被暴露胚胎的分析表明,血液动力学等物理性因素如心跳、血... 

【文章来源】：南京大学江苏省 211工程院校 985工程院校 教育部直属院校

【文章页数】：114 页

【学位级别】：博士

【文章目录】：
Abstract
中文摘要
Abbreviation
Chapter 1 A Brief Review:Cardiac valve development is determined by both genetic andenvironmental factors
    1. Function of cardiac valve in vertebrates and significance of valve development research
        1.1 Structure of mature valve
        1.2 Function of valve
        1.3 Congenital valve diseases and cues
    2. Developmental procedures of valve morphogenesis
        2.1 Valve development in amniotic vertebrate
        2.2 Valve generation in zebrafish
    3. Regulatory control of valvulogenesis
        3.1 Epigenetic factors impact early cardiac and valve formation
        3.2 Genetic factors participate in valve development
    4. Research progresses in the effect of nitrite and retinoic acid on vertebrate cardiac development and valve formation
        4.1 Research progresses in the effect of nitrite on vertebrate cardiac development and valve formation
        4.2 Research progresses in the effect of retinoic acid signaling on vertebrate cardiac development and valve formation
    References
Chapter 2 The role of sodium nitrite in cardiac valve formation of zebrafish embryos
    Summary
    Introduction
    Materials and Methods
    Results
        1. Exposure of sodium nitrite induces pericardial edema of zebrafish embryos in a dose-and time-dependent way
        2. Sodium nitrite exposure does not impact early stages of cardiac development in zebrafish embryos
        3. Sodium nitrite impacts later valve formation
        4. Sodium nitrite exposure does not impact hemodynamics of zebarfish early embryos
        5. Generation of cardiac valve progenitor cells are impacted by overdosing sodium nitrite
        6. Loss of flk1 positive cell accumulation in atrio-ventricular canal
        7. Reducing NO signaling can rescue the abnormal heart defect induced by overdosing nitrite
        8: Low concentration of oxygen in ambient water accelerates malformation of zebrafish heart development induced by sodium nitrite exposure
    Discussion
    References
Chapter 3 Retinoic acid signaling is required for zebrafish valvulogenesis
    Summary
    Intrioducntion
    Method and material
    Results
        1. Lower concentration of aldh1α2 morpholino causes specific cardiac edema rather than malformation of many other tissues
        2. Appropriate RA level in vivo is required for AVC valve leaflets formation of zebra fish embryos
        3. The effect of RA signaling on cardiac progenitor pool is not the reason for RA deficiency induced cardiac edema
        4. Earlier stages of cardiac development, before valve formation, are not disrupted in aldh1α2 morphants
        5. Hemodynamics elements, required for valve formation, are not changed under decreased RA signaling condition
        6. Invagination of endothelial cells in AVC is sensitive to endogenous RA signaling level
        7. Induction of earliest myocardial genes and specification of myocardial AVC do not require endogenous RA signaling maintain
        8. Expression of endocardial genes in AVC, required for endocardial cushion formation, are disrupted by insufficient RA signaling supply
        9. Loss of expression pattern of endocardial markers in aldh1α2 morphants can be rescued by RA addition
    Discussion
    Reference
致谢
Publication



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