Feline Model of an Inherited Craniofacial Abnormality

遗传性颅面异常的猫科动物模型

• 批准号: 6587474
• 负责人: LESLIE A LYONS
• 金额: $ 7.11万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2004-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6587474
• 关键词: animal genetic material tag; biological models; cats; craniofacial; developmental genetics; fluorescent dye /probe; gene mutation; genetic library; genetic markers; genetic models; genetic polymorphism; growth /development; homeobox genes; linkage mapping; model design /development; polymerase chain reaction

DESCRIPTION (provided by applicant): Craniofacial abnormalies in humans and the other organisms are common birth defects, although few are heritable conditions. Most research on basic body and facial structural development is interpreted from lower organisms, such as Drosophilia and zebrafish. Unlike the mouse, cats are strongly selected for facial structures. Felines are more related evolutionarily to humans than to mice, with similar genomic organization. Thus, transferring basic and clinical research on the processes that affect normal and abnormal development of craniofacial structures in the cat to humans will be extremely efficient. The long-term goal of this research is to understand the genetic components of craniofacial development in humans. The primary goal is to develop the feline into a model for human facial development. Burmese cats have a single gene defect that causes duplication of the upper maxillary region of the face. The interactions of mutations and genes for feline facial development will be more similar to humans than other current animal models. Three approaches will be used to develop the model. Specific Aim 1: Isolate feline homologs of developmental genes and gene-associated microsatellites from the cat BAC library. Genes in the HOX clusters and Sonic Hedgehog have been shown to strongly influence facial development. The hypothesis is that one of these genes causes the feline facial defect. Highly polymorphic microsatellite markers that are in juxtaposition to the genes will also be isolated from the cat. Specific Aim 2: Scan Sonic Hedgehog for causative mutations. Sonic hedgehog has a strong influence on the upper maxillary region. Specific Aim 3: Linkage analysis in feline pedigrees. Gene-associated markers will be analyzed in previously collected feline families that segregate for the cranial facial defect. This approach will support the candidate gene efforts. The hypothesis is that a linkage analysis will identify the chromosomal region for the candidate gene, focusing the search for the candidate gene. Once identified, mutation analyses of these genes in the cat or other species will lead to understanding the genetics of facial development in humans.

描述（由申请人提供）：人类和其他生物体的颅面畸形是常见的出生缺陷，尽管很少有遗传性疾病。大多数关于基本身体和面部结构发育的研究都是从低等生物（如果蝇和斑马鱼）开始的。与老鼠不同的是，猫的面部结构受到强烈的选择。猫科动物在进化上与人类的关系比与小鼠的关系更密切，它们的基因组结构相似。因此，将影响猫颅面结构正常和异常发育过程的基础和临床研究转移到人类身上将是非常有效的。这项研究的长期目标是了解人类颅面发育的遗传成分。主要目标是将猫科动物发展成为人类面部发育的模型。缅甸猫有一个单一的基因缺陷，导致重复的上颌骨地区的脸。与目前的其他动物模型相比，猫科动物面部发育的突变和基因的相互作用将更类似于人类。将使用三种方法来开发模型。具体目标1：从猫BAC文库中分离发育基因和基因相关微卫星的猫同源物。HOX簇和Sonic Hedgehog中的基因已被证明强烈影响面部发育。假设是这些基因中的一个导致了猫科动物的面部缺陷。高度多态性的微卫星标记，是并列的基因也将从猫分离。具体目标2：扫描声波刺猬致病突变。Sonic hedgehog对上颌骨区域有很强的影响。具体目标3：猫科动物家系的连锁分析。将在先前收集的猫家族中分析基因相关标志物，这些猫家族因颅面缺损而分离。这种方法将支持候选基因的努力。假设是连锁分析将确定候选基因的染色体区域，集中搜索候选基因。一旦确定，对猫或其他物种中这些基因的突变分析将有助于了解人类面部发育的遗传学。