FUNCTIONAL ANALYSIS OF GENES INVOLVED IN VERTEBRATE CRANIOFACIAL DEVELOPMENT

脊椎动物颅面发育相关基因的功能分析

• 批准号: 7491365
• 负责人: TREVOR J WILLIAMS
• 金额: $ 23.57万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7491365
• 关键词: Accounting; Affect; Animal Model; Biological Models; Candidate Disease Gene; Child; Class; Cleaved cell; Complement; Complementary DNA; Complex; Congenital Abnormality; Coupled; Data; Defect; Development; Developmental Process; Diagnosis; Embryo; Engineering; Evolution; Face; Fishes; Gene Expression; Genes; Genetic; Genetic Screening; Genomics; Goals; Growth; Head; Homologous Gene; Human; In Situ; In Situ Hybridization; Individual; Infant; Knowledge; Lead; Mediating; Microarray Analysis; Micrognathism; Microscope; Mind; Molecular; Molecular Biology Techniques; Molecular Profiling; Morphogenesis; Mus; Newborn Infant; Numbers; Online Systems; Orthologous Gene; Parents; Pattern; Phenotype; Process; Publications; Quality of life; Reagent; Regulation; Research; Resources; Role; Screening procedure; Skeleton; Specificity; Staging; Standards of Weights and Measures; Structure; System; Testing; TimeLine; Tissues; Transcript; Week; Zebrafish; base; craniofacial; critical developmental period; gene function; insight; interest; malformation; novel; oral tissue; orofacial; positional cloning; prevent; research study; spatiotemporal

About 75% of birth defects involve the head, face, and oral tissues. Although orofacial clefts and other craniofacial malformations have clear environmental and genetic causes, insufficient information exists concerning the mechanisms of craniofacial development to enable the majority of these defects to be detected or prevented pre-natally. Our goal is to develop animal models of craniofacial malformations that will lead to mechanistic insight into the diagnosis and treatment of related human birth defects. We have recently identified a large set of novel genes that are expressed during the critical stages of mouse face formation. Considerable data has accumulated over the past 25 years that orthologous genes in diverse species often share conserved functions in similar developmental processes. With these observations in mind, we intend to test our hypothesis that genes which are differentially expressed in the mouse craniofacial prominences, and which are conserved in structure and expression in the zebrafish, perform important conserved functions in the development of the vertebrate face that will be relevant to human craniofacial birth defects, including orofacial clefting and micrognathia. The zebrafish provides a very amenable system to rapidly and efficiently screen the functional importance of multiple gene candidates. Zebrafish development occurs externally and can be examined continuously under a microscope. Moreover, gene expression in the zebrafish embryo can be efficiently and easily targeted with specific anti-sense reagents, termed Morpholinos. We will perform two interrelated to Specific Aims. Aim 1. Isolation of zebrafish cDNAs corresponding to the novel and specific orofacial transcripts identified in the embryonic mouse and analysis of their expression profiles during development. Aim 2. MO based knockdown screen in zebrafish to analyze gene function in craniofacial development. Ultimately the results of this study will provide new candidates for an analysis of the underlying causes of related human birth defects. Birth defects affect ~ 3% of all infants born in the US, with about 75% of birth defects involve the head, face, and oral tissues, and the presence of a major birth defect in a newborn will frequently reduce the quality of life for both the child and the parents. Insufficient information exists concerning the mechanisms of craniofacial development to enable the majority of these defects to be detected or prevented pre-natally. We are using animal model systems to determine how normal and abnormal craniofacial development proceeds and to identify new genes that mediate face formation so that we may apply this knowledge to understand and ultimately treat the origins of human facial birth defects.

大约75%的出生缺陷涉及头部、面部和口腔组织。虽然口面裂和其他 颅面畸形有明确的环境和遗传原因，但信息不足 关于颅面发育的机制，以使大多数这些缺陷被检测到 或在出生前预防。我们的目标是建立颅面畸形的动物模型， 对相关人类出生缺陷的诊断和治疗的机械见解。我们最近 确定了一组在老鼠面部形成的关键阶段表达的新基因。 在过去的25年里，大量的数据表明，不同物种中的直向同源基因通常 在相似的发育过程中具有保守的功能。考虑到这些意见，我们打算 测试我们的假设，即在小鼠颅面神经中差异表达的基因， 其在斑马鱼中在结构和表达上是保守的，在斑马鱼中执行重要的保守功能。 脊椎动物面部的发育将与人类颅面出生缺陷有关，包括口面 裂和小颌畸形斑马鱼提供了一个非常可靠的系统，可以快速有效地筛选 多个候选基因的功能重要性。斑马鱼的发育发生在外部， 在显微镜下连续检查。此外，斑马鱼胚胎中的基因表达可以是 有效地和容易地用特异性反义试剂，称为吗啉代靶向。我们将表演两个 与具体目标相关。目标1.分离对应于新的和特异性的 在胚胎小鼠中鉴定的口面转录物及其在发育过程中的表达谱分析 发展目标2.基于MO的斑马鱼敲除筛选分析颅面基因功能 发展最终，这项研究的结果将为分析潜在的 与人类出生缺陷有关的原因。出生缺陷影响到美国出生的所有婴儿的约3%，其中约75%的出生缺陷涉及头部，面部， 和口腔组织，以及新生儿中存在重大出生缺陷通常会降低生活质量 对孩子和父母来说都是如此。关于颅面神经损伤机制的信息不足， 发展，使大多数这些缺陷能够被发现或预防产前。我们正在使用 动物模型系统，以确定正常和异常颅面发育如何进行， 确定新的基因，介导的脸形成，使我们可以应用这些知识来了解和 最终解决人类面部先天缺陷的根源。