WINGED HELIX FACTORS IN EMBRYONIC DEVELOPMENT

胚胎发育中的翼状螺旋因素

• 批准号: 6499093
• 负责人: BRIAN P HACKETT
• 金额: $ 28.67万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6499093
• 关键词: biomarker; cell differentiation; cytogenetics; developmental genetics; dynein ATPase; early embryonic stage; electron microscopy; epithelium; gene expression; gene mutation; human genetic material tag; in situ hybridization; laboratory mouse; molecular asymmetry; molecular genetics; nuclear factor kappa beta; polymerase chain reaction; single strand conformation polymorphism; transcription factor; uvea ciliary body; vertebrate embryology

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.

先天性先天缺陷是新生儿的提单原因之一 发病率和死亡率。 人类杂质综合征，例如 Kartagener综合征，通常具有致死性心脏缺陷和 睫状结构和功能缺陷。 了解起源 在这些缺陷中，需要阐明基本机制 胚胎的正常发育。 有翼螺旋转录 因素通过调节在开发过程中起重要作用 细胞分化和细胞 - 特异性基因表达。 肝细胞核因子/叉状同源物（HFH）-4是 有翼的螺旋家族在开发过程中表达了各种各样的 上皮组织。 小鼠纯合，以破坏HFH-4基因 具有左右轴不对称性和先天性异常 缺乏纤毛。 因此，HFH-4对于确定左右至关重要 轴不对称和发育过程中的纤毛细胞分化。 在拟议的研究中，我们将开始阐明 左右不对称测定和纤毛上皮细胞 HFH-4的分化。 开始理解遗传 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小鼠中纤毛上皮的结构将通过 电子显微镜以及确定的表达 与纤毛细胞分化相关的基因。差异 显示将用于识别HFH-4的潜在靶基因。 人类HFH-4基因将被隔离和表征和单一基因 链构象多态性分析用于鉴定突变 在人类HFH-4基因中。 阐明细胞和分子 调节左右不对称确定的机制具有 对脊椎动物发育和病理的重要意义 人类先天性畸形。 对差异的见解 纤毛细胞对理解 呼吸功能和病理学以及生殖功能和 不育。