PITX HOMEOBOX GENE FAMILY IN CRANIOFACIAL DEVELOPMENT

PITX 同源盒基因家族在颅面发育中的作用

• 批准号: 6651302
• 负责人: JEFFREY C MURRAY
• 金额: $ 14.87万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6651302
• 关键词: clinical research; congenital dentition disorder; congenital oral /facial /cranial defect; developmental genetics; family genetics; gene environment interaction; gene interaction; gene mutation; genetic mapping; genetically modified animals; homeobox genes; human subject; laboratory mouse; phenotype

Human development is a complex process involving multiple gene interactions at various stages of embryogenesis and with important environmental overlays. In the last few years, the role of transcription factors in early development and the impact that disruptions in these genes can have on normal structures has become increasingly evident. We have recently identified the human RIEG1 (PITX) gene as a novel bicoid- class homeobox gene responsible for Rieger syndrome, which has anterior chamber defects, dental hypoplasia and umbilical abnormalities as primary manifestations. A second member of this family (PITX3) has just been identified in our laboratory in which a mutation causes the disorder anterior segment mesenchymal dysgenesis (ASMD). In this proposal, we will expand our studies of these transcription factors, through identification of additional human craniofacial disturbances caused by abnormalities in these genes and by detailed studies of the genes developmental cascade. Specific goals of the project will include: 1) additional characterization of the Rieger class genes, including their DNA structure, the identification of new class members and of gene homologous to the recognized regulatory sequences. Further characterization of families and individuals, with a particular focus on those whose phenotype includes craniofacial anomalies will also be carried out; 2) expression-based studies will be performed that will included tissue-specific studies involving the mouse model; 3) the use of transgenic animals as a model systems for the study of epistatic interactions, including the development of knockout mice for two of the Rieger-class genes and the initiation of complementation studies using Rieger-related genes and genes with similar or complementary expression patters. The outcome of this project will be an expansion of our understanding of the causes of facial structural defects, as well as a detailed understanding of the developmentally biology of a new class of homeobox genes shown to be critical in development. Models will be developed that can be used for studies of gene-gene and gene-environment interactions to further our insights into basic biology, therapeutics and prevention. The correlation of expanded phenotypes with specific mutations and the ability to study these for gene-gene and gene- environment interaction affords a opportunity for a comprehensive understanding of a new class of homeobox genes for their role in human birth defects and adult disease. This project will directly interact with Project 3 (Russo) which will study protein-protein interactions of the PITX genes and interface with projects 4 and 5 and the clinical and molecular cores, as well.

人类发育是一个复杂的过程，涉及胚胎发育各个阶段的多基因相互作用，并与重要的环境重叠。在过去的几年里，转录因子在早期发育中的作用以及这些基因的破坏对正常结构的影响已经变得越来越明显。我们最近鉴定了人RIEG 1（PITX）基因作为一种新的bicoid类同源盒基因，其负责Rieger综合征，其具有前房缺损、牙齿发育不全和脐部异常作为主要表现。这个家族的第二个成员（PITX 3）刚刚在我们的实验室中被发现，其中一个突变导致了眼前段间充质发育不全（ASMD）。在这项建议中，我们将扩大我们的研究，这些转录因子，通过识别额外的人类颅面障碍所造成的异常，这些基因和详细的研究基因发育级联。该项目的具体目标将包括：1）Rieger类基因的额外表征，包括其DNA结构，新类成员的鉴定和与公认的调控序列同源的基因的鉴定。还将对家族和个体进行进一步表征，特别关注那些表型包括颅面异常的家族和个体; 2）将进行基于表达的研究，包括涉及小鼠模型的组织特异性研究; 3）使用转基因动物作为研究上位相互作用的模型系统，包括开发两种Rieger类基因的敲除小鼠和使用Rieger相关基因和具有相似或互补表达模式的基因开始互补研究。该项目的成果将扩大我们对面部结构缺陷原因的理解，以及对一类新的同源异型盒基因的发育生物学的详细理解，这些基因在发育中至关重要。将开发可用于研究基因-基因和基因-环境相互作用的模型，以进一步加深我们对基础生物学、治疗学和预防的认识。扩展表型与特定突变的相关性以及研究这些基因-基因和基因-环境相互作用的能力为全面了解一类新的同源异型盒基因在人类出生缺陷和成人疾病中的作用提供了机会。该项目将与项目3（Russo）直接互动，该项目将研究PITX基因的蛋白质-蛋白质相互作用，并与项目4和5以及临床和分子核心接口。