發(fā)布時間：2022-01-20 16:00

　　瓣膜通常位于心臟的流出道和房室通道處,在心臟內部起著防止血液倒流的作用。由于瓣膜結構的復雜性和生成時間的長期性使得瓣膜發(fā)生很容易受到致畸因子的影響,因此先天性瓣膜疾病在成活出生嬰兒中發(fā)病比例很高。但目前只有20%左右的先心病可以診斷出確切的病因。因此,研究環(huán)境因子和遺傳因素在瓣膜發(fā)生過程中的作用對防治新生兒先天性心臟發(fā)育缺陷有重要的意義。亞硝酸鹽是一種常用的食品添加劑,除大量存在在環(huán)境中外,亦廣泛分布于我們身體的多種組織和器官中。通過參與體內的硝酸鹽-亞硝酸鹽-一氧化氮穩(wěn)態(tài)發(fā)揮著重要的生物和生理學作用。已知過量的亞硝酸鹽可對人類健康產生導致多種毒理作用,但其對脊椎動物的心臟瓣膜發(fā)生的影響迄今尚未見報道,在本研究中,我們利用了在研究心血管系統(tǒng)發(fā)育方面具有獨特優(yōu)勢的模式動物斑馬魚,探討了亞硝酸鹽在脊椎動物早期胚胎發(fā)生過程中對瓣膜發(fā)育的影響。通過將斑馬魚胚胎曝露在亞硝酸鹽的環(huán)境中生長,我們的研究發(fā)現(xiàn)亞硝酸鹽會以濃度依賴的方式致脊椎動物胚胎心臟出現(xiàn)心臟水腫等發(fā)育異常,其作用的時間窗自36 hpf（受精后36小時）起。對24hpf至48hpf被暴露胚胎的分析表明,血液動力學等物理性因素如心跳、血... 

【文章來源】：南京大學江蘇省 211工程院校 985工程院校 教育部直屬院校

【文章頁數(shù)】：114 頁

【學位級別】：博士

【文章目錄】：
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
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