NOTCH SIGNALING PATHWAY LIGANDS IN CARDIOVASCULAR DISEASE

心血管疾病中的 NOTCH 信号通路配体

基本信息

  • 批准号:
    6302546
  • 负责人:
  • 金额:
    $ 17.17万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2000
  • 资助国家:
    美国
  • 起止时间:
    2000-02-01 至 2000-12-31
  • 项目状态:
    已结题

项目摘要

(Adapted from the Applicant's Abstract) Identification of genes causing human cardiac disease provides insight into the molecular pathways involved in heart development. The investigators have recently identified Jagged1 (JAG1) as the disease gene causing Alagille syndrome, a genetic disorder associated with heart, liver, and several other anomalies. JAG1 is a ligand in the Notch signaling pathway, shown in multiple organisms to be involved in cell fate determination. Alagille syndrome is a dominant disorder, with extreme variability in the expression of phenotypic features. Some individuals with JAG1 mutations have only a single clinical feature, rather than the multi- system involvement characteristic of Alagille syndrome, which led the investigators to hypothesize that JAG1 mutations would be identified in patients with isolated heart disease. The preliminary data support this hypothesis, as the investigators have identified three patients with cardiac disease and JAG1 mutations who do not manifest the liver abnormalities associated with Alagille syndrome. The investigators will extend this work to study a cohort of patients to determine the frequency of JAG1 mutations associated with cardiac defects. In order to understand how JAG1 is involved in cardiovascular development, the investigators will analyze location and timing of JAG1 expression in the developing mouse embryo. The investigators will also address the mechanism by which mutations in JAG1 cause heart disease. In Drosophila, mutations in Notch ligands which cause truncated proteins similar to those predicted in Alagille syndrome patients, act in a dominant negative fashion. However, there is compelling data from human studies that the mechanism for the effect of JAG1 is haploinsufficiency. The investigators propose to overexpress the mutations seen in Alagille syndrome patients in the mouse embryo and determine their effect on early vascular development. The investigators further propose that other members of the Notch signaling pathway may be associated with cardiac abnormalities. The Notch ligand Delta has recently been mapped to 6q27, a region of the genome associated with cardiac disease in patients deleted for this region. The investigators will determine if Delta is the gene responsible for heart disease in these patients. If they are unable to show a role for Delta, they will use a positional cloning approach to identify other gene(s) associated with cardiac disease from 6q27. In summary, this work will provide an increased understanding of the role of JAG1 in normal and abnormal development of the heart, and lay the foundation for identifying additional genes contributing to cardiac disease.
(改编自申请人摘要)导致人类心脏病的基因的鉴定提供了对心脏发育中涉及的分子途径的深入了解。 研究人员最近确定Jagged1(JAG1)是导致Alagille综合征的疾病基因,Alagille综合征是一种与心脏,肝脏和其他几种异常相关的遗传疾病。 JAG1是Notch信号通路中的配体,在多种生物体中显示参与细胞命运决定。Alagille综合征是一种显性疾病,在表型特征的表达中具有极端的变异性。 一些具有JAG 1突变的个体只有单一的临床特征,而不是阿拉吉耶综合征的多系统受累特征,这导致研究人员假设JAG 1突变将在孤立的心脏病患者中被鉴定出来。 初步数据支持这一假设,因为研究人员已经确定了三名患有心脏病和JAG1突变的患者,他们没有表现出与Alagille综合征相关的肝脏异常。 研究人员将扩展这项工作,研究一组患者,以确定与心脏缺陷相关的JAG1突变的频率。 为了了解JAG1如何参与心血管发育,研究人员将分析JAG1在发育中的小鼠胚胎中表达的位置和时间。 研究人员还将探讨JAG1突变导致心脏病的机制。 在果蝇中,Notch配体的突变导致截短的蛋白质类似于Alagille综合征患者中预测的蛋白质,以显性负性方式起作用。 然而,来自人类研究的令人信服的数据表明,JAG1的作用机制是单倍不足。 研究人员建议在小鼠胚胎中过表达Alagille综合征患者中观察到的突变,并确定它们对早期血管发育的影响。 研究人员进一步提出,Notch信号通路的其他成员可能与心脏异常有关。 Notch配体Delta最近被定位于6q27,这是与心脏病患者相关的基因组区域,该区域被删除。 研究人员将确定Delta是否是导致这些患者心脏病的基因。 如果他们无法显示Delta的作用,他们将使用定位克隆方法来识别6q27与心脏病相关的其他基因。 总之,这项工作将增加对JAG1在心脏正常和异常发育中的作用的理解,并为鉴定导致心脏疾病的其他基因奠定基础。

项目成果

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Nancy Bettina Spinner其他文献

Nancy Bettina Spinner的其他文献

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{{ truncateString('Nancy Bettina Spinner', 18)}}的其他基金

Resolving Uncertainty in Alagille Syndrome Diagnostics
解决阿拉吉尔综合征诊断中的不确定性
  • 批准号:
    10734881
  • 财政年份:
    2023
  • 资助金额:
    $ 17.17万
  • 项目类别:
Training Program in the Genetic Basis of Pediatric Gastrointestinal Disorders
儿科胃肠道疾病遗传基础培训计划
  • 批准号:
    8883521
  • 财政年份:
    2014
  • 资助金额:
    $ 17.17万
  • 项目类别:
Training Program in the Genetic Basis of Pediatric Gastrointestinal Disorders
儿科胃肠道疾病遗传基础培训计划
  • 批准号:
    8666845
  • 财政年份:
    2014
  • 资助金额:
    $ 17.17万
  • 项目类别:
Genetic Modifiers of Liver Disease Severity in Alagille Syndrome
阿拉吉尔综合征肝病严重程度的基因修饰
  • 批准号:
    7883529
  • 财政年份:
    2009
  • 资助金额:
    $ 17.17万
  • 项目类别:
Genetic Modifiers of Liver Disease Severity in Alagille Syndrome
阿拉吉尔综合征肝病严重程度的基因修饰
  • 批准号:
    7661203
  • 财政年份:
    2009
  • 资助金额:
    $ 17.17万
  • 项目类别:
Genetic Modifiers of Liver Disease Severity in Alagille Syndrome
阿拉吉尔综合征肝病严重程度的基因修饰
  • 批准号:
    8502652
  • 财政年份:
    2009
  • 资助金额:
    $ 17.17万
  • 项目类别:
Genetic Modifiers of Liver Disease Severity in Alagille Syndrome
阿拉吉尔综合征肝病严重程度的基因修饰
  • 批准号:
    8097573
  • 财政年份:
    2009
  • 资助金额:
    $ 17.17万
  • 项目类别:
Genetic Modifiers of Liver Disease Severity in Alagille Syndrome
阿拉吉尔综合征肝病严重程度的基因修饰
  • 批准号:
    8306850
  • 财政年份:
    2009
  • 资助金额:
    $ 17.17万
  • 项目类别:
Genetic Modifiers of Liver Disease Severity in Alagille Syndrome
阿拉吉尔综合征肝病严重程度的基因修饰
  • 批准号:
    8090799
  • 财政年份:
    2009
  • 资助金额:
    $ 17.17万
  • 项目类别:
NOTCH SIGNALING PATHWAY LIGANDS IN CARDIOVASCULAR DISEASE
心血管疾病中的 NOTCH 信号通路配体
  • 批准号:
    6565108
  • 财政年份:
    2002
  • 资助金额:
    $ 17.17万
  • 项目类别:

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  • 财政年份:
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