COMPARATIVE GENETICS OF GLI FUNCTION

GLI 功能的比较遗传学

• 批准号: 6829985
• 负责人: ALEXANDER F SCHIER
• 金额: $ 42.25万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-28 至 2005-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6829985
• 关键词: biochemical evolution; comparative genomic hybridization; congenital disorders; congenital nervous system disorder; congenital oral /facial /cranial defect; developmental genetics; disease /disorder model; functional /structural genomics; gene complementation; gene expression; gene mutation; gene targeting; genetically modified animals; histology; laboratory mouse; model design /development; transcription factor; zebrafish

DESCRIPTION (provided by applicant): The role of developmental control genes in human birth defects has raised the questions if orthologous genes have conserved or divergent functions and how insights gained from animal models can be applied to human. To address these questions, the investigators propose to perform a comparative genetic analysis of the functions of Gli1, Gli2 and Gli3 transcription factors that mediate hedgehog signaling. In previous studies, they have discovered or engineered mutations in human, mouse and zebrafish gli genes. In all three systems, gli mutations lead to cranio-facial and central nervous system defects. Phenotypic comparisons have suggested that these genes share some functional properties, but that their roles also differ. The long-range goal of the investigators' studies is to determine if the seemingly divergent functions of different gli genes are due to differences in Gli proteins or due to other species-specific factors. Using mouse and zebrafish as model systems, they will 1) analyze the activity of zebrafish and human Gli proteins in mouse using knock-in approaches; 2) analyze the activity of mouse and human Gli proteins in zebrafish using misexpression and complementation approaches; and 3) create animal models for human birth defects and analyze the activity of human gli mutations in zebrafish and mouse. These comparative genetic studies will allow detailed insights into the conservation and divergence of orthologous genes and will test the value of animal models in understanding human birth defects.

描述（由申请人提供）：发育控制基因在人类出生缺陷中的作用提出了问题，即直系同源基因是否具有保守或发散功能，以及如何将从动物模型中获得的见解应用于人类。为了解决这些问题，研究人员建议对介导刺猬信号的GLI1，GLI2和GLI3转录因子的功能进行比较遗传分析。在先前的研究中，他们在人，小鼠和斑马鱼Gli基因中发现或设计了突变。在所有三个系统中，GLI突变导致颅神经系统缺陷。表型比较表明这些基因具有某些功能特性，但它们的作用也有所不同。研究人员研究的远程目标是确定不同GLI基因的看似不同的功能是由于GLI蛋白的差异或其他物种特异性因素所致。他们将使用小鼠和斑马鱼作为模型系统，将使用敲入方法分析小鼠在小鼠中斑马鱼和人Gli蛋白的活性； 2）使用Misexpression和补充方法分析小鼠和人Gli蛋白在斑马鱼中的活性； 3）创建用于人类出生缺陷的动物模型，并分析斑马鱼和小鼠中人类Gli突变的活性。这些比较遗传研究将详细介绍直系同源基因的保护和差异，并将测试动物模型在理解人类出生缺陷中的价值。