Cell-substrate interaction in craniofacial morphogenesis

颅面形态发生中的细胞-基质相互作用

• 批准号: 6987369
• 负责人: BARRY D SHUR
• 金额: $ 36.34万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6987369
• 关键词: alternatives to animals in research; biological signal transduction; cell adhesion molecules; cell cell interaction; cell migration; cell surface receptors; craniofacial; cytoplasm; cytoskeletal proteins; cytoskeleton; embryogenesis; enzyme activity; enzyme substrate; galactosyltransferases; gene expression; genetically modified animals; histogenesis; in situ hybridization; polymerase chain reaction; site directed mutagenesis; terminal nick end labeling; zebrafish

DESCRIPTION (provided by applicant): The mechanisms that underlie morphogenetic cell movements are responsible for many of the most common congenital malformations, including those that impact craniofacial development. There has been circumstantial evidence for many years suggesting that complex carbohydrates play critically important roles during morphogenesis; however, our understanding of their function during mammalian development is limited to anecdotal and descriptive studies. The enzymes responsible for synthesizing complex carbohydrates are the glycosyltransferase, of which there are -150 known polypeptides. Consequently, the current mammalian model systems are inappropriate for detailed analysis of their function, since without more information, there is no way to determine which particular glycosyltransferases are important. This necessitates the development of better model systems to address glycosyltransferase function during development, in general, and during craniofacial morphogenesis, in particular. Towards this end, the zebrafish system proves to be an excellent model system in which to characterize the expression and function of specific glycosyltransferases during development. Preliminary studies demonstrate that specific members of the IS-galactosyl and afucosyltransferases families are expressed during zebrafish embryogenesis, and furthermore, that downregulating their expression leads to severe developmental anomalies, ranging from defects in early embryonic patterning to localized defects in craniofacial development. In this revised renewal application, we will pursue a more detailed analysis of glycosyltransferase expression and function during zebrafish development. Studies will determine if glycosyltransferases participate in defined molecular pathways and/or if they are related to mutations known to affect embryonic development and/or craniofacial morphogenesis. Finally, their mode of action will be examined through traditional biochemical approaches. It is anticipated, that these results will identify glycosyltransferases that play key roles in early embryonic and craniofacial development, and which can then be analyzed in appropriate mammalian model systems.

描述（由申请人提供）： 构成形态发生细胞运动基础的机制是许多最常见的先天性畸形的原因，包括那些影响颅面发育的畸形。多年来，有间接证据表明，复合碳水化合物在形态发生过程中发挥着至关重要的作用;然而，我们对它们在哺乳动物发育过程中的功能的理解仅限于轶事和描述性研究。负责合成复杂碳水化合物的酶是糖基转移酶，其中已知有约150种多肽。因此，目前的哺乳动物模型系统不适合详细分析其功能，因为没有更多的信息，没有办法确定哪些特定的糖基转移酶是重要的。这就需要开发更好的模型系统，以解决糖基转移酶的功能在发展过程中，一般来说，在颅面形态，特别是。为此，斑马鱼系统被证明是一个很好的模型系统，在其中表征特定的糖基转移酶在发展过程中的表达和功能。初步研究表明，特定成员的IS-半乳糖基和无岩藻糖基转移酶家族在斑马鱼胚胎发育过程中表达，而且，下调其表达导致严重的发育异常，从早期胚胎图案的缺陷到颅面发育的局部缺陷。在这个修订后的更新申请中，我们将对斑马鱼发育过程中糖基转移酶的表达和功能进行更详细的分析。研究将确定糖基转移酶是否参与确定的分子途径和/或它们是否与已知影响胚胎发育和/或颅面形态发生的突变有关。最后，他们的行动模式将通过传统的生物化学方法进行检查。预计这些结果将鉴定在早期胚胎和颅面发育中起关键作用的糖基转移酶，然后可以在适当的哺乳动物模型系统中进行分析。