Genetic Complementation of a Mouse Model for PWS

PWS 小鼠模型的遗传互补

基本信息

  • 批准号:
    7420992
  • 负责人:
  • 金额:
    $ 27.46万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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):普瑞德-威利综合征是一种神经行为障碍,其特征是婴儿张力过低、身材矮小、新生儿发育不全,随后伴有强迫行为、嗜食和肥胖。PWS是由位于15q11-13的几个印迹基因的表达缺失引起的,可能是由于母亲的15q二体,父亲的一组PWS基因缺失,或者父亲的微缺失消除了父亲基因表达所必需的印迹中心(IC)。我们之前通过靶向删除IC创建了PWS小鼠模型。携带父亲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。在之前的资助期内,我们发现一些菌株的母亲所生的IC缺失幼崽存活下来,最终为研究PWS基因在成虫、胎儿和出生后阶段的作用提供了机会。PWS-IC缺失小鼠产后早期死亡的病因是复杂的。虽然不能茁壮成长是一个原因,但由Necdin缺乏引起的呼吸问题也是一个重要因素。此外,我们还发现了多基因座失败的证据。在具体目标1中,我们将使用表达PWS基因组的BAC转基因进行互补,以确定PWS小鼠模型中与发育失败有关的位点,并确认Necdin在出生后早期死亡中的作用。肥胖和潜在的贪食是PWS的显著特征。具体目的2提出探索成年PWS小鼠发生肥胖的各种条件,并研究PWS基因在肥胖进展中的作用。已知许多印迹基因与胎儿生长有关。我们最近发现,IC缺失胚胎会降低胎儿生长,并且一些PWS基因在胎盘中表达。在具体的目标3中,我们将结合现有的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,这项研究将显著有助于理解个体基因在复杂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。

项目成果

期刊论文数量(0)
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JAMES L RESNICK其他文献

JAMES L RESNICK的其他文献

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{{ truncateString('JAMES L RESNICK', 18)}}的其他基金

Imprinting defects leading to Angelman and Prader Willi syndromes
导致天使威利综合征和普莱德威利综合征的印记缺陷
  • 批准号:
    8613914
  • 财政年份:
    2013
  • 资助金额:
    $ 27.46万
  • 项目类别:
Imprinting defects leading to Angelman and Prader Willi syndromes
导致天使威利综合征和普莱德威利综合征的印记缺陷
  • 批准号:
    8714089
  • 财政年份:
    2013
  • 资助金额:
    $ 27.46万
  • 项目类别:
GENETIC ANALYSIS OF FETAL GERM CELL DEVELOPMENT
胎儿生殖细胞发育的遗传分析
  • 批准号:
    6363448
  • 财政年份:
    2000
  • 资助金额:
    $ 27.46万
  • 项目类别:
GENETIC ANALYSIS OF FETAL GERM CELL DEVELOPMENT
胎儿生殖细胞发育的遗传分析
  • 批准号:
    6033647
  • 财政年份:
    2000
  • 资助金额:
    $ 27.46万
  • 项目类别:
GENETIC ANALYSIS OF FETAL GERM CELL DEVELOPMENT
胎儿生殖细胞发育的遗传分析
  • 批准号:
    6521282
  • 财政年份:
    2000
  • 资助金额:
    $ 27.46万
  • 项目类别:
GENETIC ANALYSIS OF FETAL GERM CELL DEVELOPMENT
胎儿生殖细胞发育的遗传分析
  • 批准号:
    6637052
  • 财政年份:
    2000
  • 资助金额:
    $ 27.46万
  • 项目类别:
Genetic Complementation of a Mouse Model for PWS
PWS 小鼠模型的遗传互补
  • 批准号:
    7840388
  • 财政年份:
    1999
  • 资助金额:
    $ 27.46万
  • 项目类别:
Genetic Complementation of a Mouse Model for PWS
PWS 小鼠模型的遗传互补
  • 批准号:
    7211969
  • 财政年份:
    1999
  • 资助金额:
    $ 27.46万
  • 项目类别:
Genetic Complementation of a Mouse Model for PWS
PWS 小鼠模型的遗传互补
  • 批准号:
    7614501
  • 财政年份:
    1999
  • 资助金额:
    $ 27.46万
  • 项目类别:
Mouse Models of Human PWS/AS Imprinting Center Mutations
人类 PWS/AS 印记中心突变的小鼠模型
  • 批准号:
    6846248
  • 财政年份:
    1997
  • 资助金额:
    $ 27.46万
  • 项目类别:

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