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WINGED HELIX FACTORS IN EMBRYONIC DEVELOPMENT

胚胎发育中的翼状螺旋因素

基本信息

批准号：
6629095
负责人：
BRIAN P HACKETT
金额：
$ 29.53万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-02-01 至 2005-01-31
项目状态：
已结题

项目摘要

Congenital birth defects are one of the lading causes of neonatal morbidity and mortality. Human heterotaxy syndromes, such as Kartagener syndrome, often have associated lethal cardiac defects and defects in ciliary structure and function. Understanding the origins of these defects requires an elucidation of the mechanisms underlying the normal development of the embryo. Winged helix transcription factors play important roles during development by regulating cellular differentiation and cell - specific gene expression. Hepatocyte nuclear factor/forkhead homologue (HFH) - 4 is a member of the winged helix family expressed during development in a variety of epithelial tissues. Mice homozygous for disruption of the hfh-4 gene have congenital abnormalities of the left-right axis asymmetry and lack cilia. HFH-4 is thus essential for determination of left-right axis asymmetry and ciliated cell differentiation during development. In the proposed studies, we will begin to elucidate the mechanisms of left-right asymmetry determination and ciliated epithelial cell differentiation by HFH-4. To begin to understand the genetic pathways involved in left-right asymmetry the early embryonic pattern of HFH-4 expression will be determined and the expression patterns of other ~left-right~ genes will be studied in hfh-4 mice. The structure of ciliated epithelium in hfh-4 mice will be studied by electron microscopy, as well as determination of the expression of genes associated with ciliated cell differentiation.. Differential display will be used to identify potential target genes for HFH-4. The human HFH-4 gene will be isolated and characterized and single chain conformation polymorphism analysis used to identify mutations in the human HFH-4 gene. Elucidating the cellular and molecular mechanisms regulating the determination of left-right asymmetry has great significance for vertebrate development and the pathology of human congenital malformations. Insights into the differentiation of ciliated cells have important implications for understanding the respiratory function and pathology and for reproductive function and infertility.

先天性出生缺陷是导致新生儿出生缺陷的原因之一发病率和死亡率。人类异位综合症，例如卡塔格纳综合征，通常伴有致命的心脏缺陷和睫状体结构和功能缺陷。了解起源需要阐明这些缺陷的潜在机制胚胎的正常发育。翼状螺旋转录因素通过调节在发育过程中发挥重要作用细胞分化和细胞特异性基因表达。肝细胞核因子/叉头同源物 (HFH) - 4 是有翼螺旋家族在发育过程中以多种形式表达上皮组织。 hfh-4 基因破坏的纯合小鼠有先天性左右轴不对称异常，缺乏纤毛。因此 HFH-4 对于左右判断至关重要发育过程中的轴不对称和纤毛细胞分化。在拟议的研究中，我们将开始阐明其机制左右不对称性测定及纤毛上皮细胞通过 HFH-4 进行分化。开始了解遗传参与左右不对称的途径早期胚胎模式将确定 HFH-4 表达的表达模式其他〜左右〜基因将在 hfh-4 小鼠中进行研究。这 hfh-4小鼠纤毛上皮的结构将通过以下方法进行研究电子显微镜，以及表达的测定与纤毛细胞分化相关的基因.. 差异显示器将用于鉴定 HFH-4 的潜在靶基因。人类 HFH-4 基因将被分离和表征，并且是单一的用于识别突变的链构象多态性分析存在于人类 HFH-4 基因中。阐明细胞和分子调节左右不对称性的机制对于脊椎动物的发育和病理学具有重要意义人类先天畸形。洞察差异化纤毛细胞对于理解纤毛细胞具有重要意义呼吸功能和病理学以及生殖功能和不孕症。