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.

先天性出生缺陷是新生儿死亡的主要原因之一 发病率和死亡率。 人类内脏异位综合征，如 Kartagener综合征通常伴有致命的心脏缺陷， 睫状体结构和功能的缺陷。 了解起源 这些缺陷需要阐明的机制， 胚胎的正常发育。 翅膀状螺旋转录 因子通过调节，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是一个成员， 有翼螺旋家族在各种发育过程中表达， 上皮组织 hfh-4基因破坏纯合子小鼠 有先天性左右轴不对称的异常， 无纤毛。 因此，HFH-4对于确定左-右 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 左右不对称测定与纤毛上皮细胞 通过HFH-4进行区分。 为了开始了解基因 参与左右不对称的通路早期胚胎模式 HFH-4表达的表达模式将被确定， 将在HFH-4小鼠中研究其它左右基因。 的 将通过以下方法研究HFH-4小鼠中纤毛上皮的结构： 电子显微镜，以及表达的测定， 与纤毛细胞分化相关的基因。 微分 展示将用于鉴定HFH-4的潜在靶基因。 人HFH-4基因将被分离和表征， 用于识别突变的链构象多态性分析 在人类HFH-4基因中。 阐明细胞和分子 调节左右不对称决定的机制， 对脊椎动物的发育和 人类先天畸形 深入了解 纤毛细胞对于理解 呼吸功能和病理学以及生殖功能， 不孕