Genetic Complementation of a Mouse Model for PWS

PWS 小鼠模型的遗传互补

• 批准号: 7211969
• 负责人: JAMES L RESNICK
• 金额: $ 28.02万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-17 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211969
• 关键词: 15q; Adult; Age; Animal Model; Birth Weight; Cessation of life; Child; Chromosomes; Complement; Complex; Condition; Data; Defect; Development; Disease; Embryo; Etiology; Exhibits; Failure to Thrive; Fatty acid glycerol esters; Fetal Growth; Fetal Growth Retardation; Fetus; Funding; Gene Expression; Genes; Genetic; Growth; Human; Hyperphagia; Individual; Infant; Inherited; Knock-out; Low Birth Weight Infant; Modeling; Morbidity - disease rate; Mothers; Mus; Muscle hypotonia; Neonatal; Numbers; Obesity; Obsessive compulsive behavior; Patients; Phase; Phenotype; Placenta; Placentation; Play; Prader-Willi Syndrome; Pregnancy; Regulation; Research; Research Personnel; Resources; Role; Staging; Testing; Transgenes; Transgenic Organisms; Weaning; Week; Weight; Weight Gain; feeding; fetal; imprint; infancy; insight; microdeletion; mouse model; necdin; neurobehavioral disorder; paternal imprint; postnatal; prevent; programs; pup; respiratory; size; trait

DESCRIPTION (provided by applicant): Prader-Willi syndrome is a neurobehavioral disorder characterized by infantile hypotonia, short stature, and neonatal failure to thrive followed by obsessive-compulsive behavior, hyperphagia, and obesity. PWS results from loss of expression of several imprinted genes located at 15q11-13 and can arise from maternal 15q disomy, paternal deletion of a group of PWS genes, or paternal microdeletions removing an imprinting center (IC) necessary for paternal gene expression. We previously created a PWS mouse model by targeted deletion of the IC. Pups bearing a paternal IC deletion exhibit a failure to thrive inevitably leading to death in the first postnatal week. In the previous funding period, we found that death of IC deletion pups born to mothers of some strains survive, finally providing an opportunity to investigate the role of PWS genes in adult, as well as fetal and postnatal stages. The etiology of early postnatal death in PWS-IC deletion mice is complex. While failure to thrive is one cause, respiratory problems caused by Necdin deficiency is also an important factor. Additionally, we have found evidence for multi-locus failure to thrive. In specific aim 1, we will use complementation by BAC transgenes expressing groups of PWS genes to identify loci involved in failure to thrive and to confirm the role of Necdin in early postnatal death in PWS mouse models. Obesity and underlying hyperphagia are salient aspects of PWS. Specific aim 2 proposes to explore various conditions to develop obesity in surviving adult PWS mice, and investigate the roles of PWS genes in progression to obesity. A number of imprinted genes are known to be involved in fetal growth. We have recently found that IC deletion embryos have decreased fetal growth and that some PWS genes are expressed in the placenta. In specific aim 3, we will combine existing PWS models and BAC transgene complementation to test the role of subsets of PWS genes in placental development. We anticipate that this research will significantly contribute to understanding the roles of individual genes in complex PWS traits, refine mouse models of the disease, and provide new insights into growth and obesity.

描述（由申请人提供）：Prader-Willi综合征是一种神经行为障碍，其特征为婴儿张力减退、身材矮小和新生儿发育不良，随后出现强迫行为、暴食和肥胖。PWS由位于15 q11 -13的几个印记基因的表达缺失引起，并且可以由母本15 q二体性、父本一组PWS基因的缺失或父本微缺失去除父本基因表达所必需的印记中心（IC）引起。我们先前通过IC的靶向缺失创建了PWS小鼠模型。携带父源IC缺失的幼崽表现出无法茁壮成长，不可避免地导致出生后第一周死亡。在之前的资助期间，我们发现某些菌株的母亲所生的IC缺失幼崽的死亡存活，最终提供了一个机会来研究PWS基因在成年以及胎儿和出生后阶段的作用。PWS-IC缺失小鼠产后早期死亡的病因很复杂。虽然不能茁壮成长是一个原因，但Necdin缺乏引起的呼吸问题也是一个重要因素。此外，我们还发现了多位点未能茁壮成长的证据。在具体目标1中，我们将使用表达PWS基因组的BAC转基因的互补来鉴定参与不能茁壮成长的基因座，并确认Necdin在PWS小鼠模型中出生后早期死亡中的作用。肥胖和潜在的摄食过多是PWS的突出方面。具体目标2提出探索存活的成年PWS小鼠中发展肥胖的各种条件，并研究PWS基因在肥胖进展中的作用。已知许多印记基因与胎儿生长有关。我们最近发现IC缺失的胚胎降低了胎儿的生长，并且一些PWS基因在胎盘中表达。在具体目标3中，我们将结合联合收割机现有的PWS模型和BAC转基因互补来测试PWS基因亚群在胎盘发育中的作用。我们预计，这项研究将大大有助于了解单个基因在复杂PWS性状中的作用，完善该疾病的小鼠模型，并为生长和肥胖提供新的见解。