Dissecting the role of DNA Ligase 1 in Huntington's disease

剖析 DNA 连接酶 1 在亨廷顿舞蹈病中的作用

基本信息

  • 批准号:
    10733111
  • 负责人:
  • 金额:
    $ 63.07万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-25 至 2028-06-30
  • 项目状态:
    未结题

项目摘要

Huntington’s disease (HD) is a devastating and fatal neurodegenerative disorder caused by the expansion of a polymorphic CAG repeat in the HTT gene. Although the underlying genetic mutation was discovered over 25 years ago, there is still no cure or effective treatment despite extensive efforts. The CAG repeat mutation undergoes time- and CAG length-dependent somatic expansion and recent genome-wide association studies (GWAS) support somatic CAG expansion as the first step of the pathogenic process, required to elicit cellular toxicity and ultimately clinical disease. GWAS identified several genes involved in DNA repair as modifiers of age of onset, among which is LIG1, encoding DNA ligase 1. The biological function of DNA ligase 1 implicates it in somatic CAG expansion, however this gene may also alter processes that impact on cellular toxicity. Overall, the mechanistic underpinnings of disease modification remain obscure. Independent LIG1 modifier chromosomes can be distinguished in the human genetic data: one, tagged by a predicted deleterious SNP encoding a K854N substitution, is onset-delaying, while another is associated with increased LIG1 expression and is onset-hastening. In this study, we will perform experiments to test hypotheses rooted in human genetic data to understand the functional consequences of these LIG1 modifier effects. In Aim 1 we will use a knock-in mouse model of HD to test the impact of the K>N substitution mutation introduced into the mouse Lig1 gene, and to test the impact of Lig1 upregulation, on somatic CAG expansion and phenotypic expression. In Aim 2 we will use HD patient-derived and isogenic neuronal progenitor cells and neurons harboring LIG1 modifier alleles to identify their cellular and molecular consequences and to test their impacts on phenotypes elicited by the HTT mutation. In Aim 3 we will perform biochemical, structural and functional analyses of the LIG1 K845N variant. Together, these experiments will provide novel insight into mechanisms by which genetic variation in LIG1 modifies disease in patients, ultimately revealing therapeutic avenues that can be pursued for disease- modifying treatments.
亨廷顿氏病(HD)是一种毁灭性的和致命的神经退行性疾病,其由一种神经系统疾病的扩张引起。 HTT基因中的多态性CAG重复。虽然潜在的基因突变是在25岁以上的时候发现的, 多年前,尽管作出了广泛的努力,但仍然没有治愈或有效的治疗方法。CAG重复突变 经历了时间和CAG长度依赖性的体细胞扩增和最近的全基因组关联研究 (GWAS)支持体细胞CAG扩增作为致病过程的第一步,这是引起细胞凋亡所必需的。 毒性和最终的临床疾病。GWAS鉴定了几个参与DNA修复的基因, 发病年龄,其中LIG 1,编码DNA连接酶1。DNA连接酶1的生物学功能提示 它在体细胞CAG扩增中,然而该基因也可能改变影响细胞毒性的过程。 总体而言,疾病修饰的机制基础仍然模糊不清。独立LIG 1修饰剂 在人类遗传数据中,可以区分出两种染色体:一种是被预测的有害SNP标记的染色体, 编码K854 N置换的一个基因是延迟发作的,而另一个基因与LIG 1表达增加有关 并且具有加速发病的作用。在这项研究中,我们将进行实验,以测试植根于人类遗传学的假设, 数据来理解这些LIG 1修饰剂效应的功能后果。在目标1中,我们将使用敲入 HD小鼠模型以测试引入小鼠Lig 1基因的K>N置换突变的影响, 并测试Lig 1上调对体细胞CAG扩增和表型表达的影响。在目标2中 我们将使用HD患者来源的和同基因的神经元祖细胞和携带LIG 1修饰物的神经元 等位基因,以确定它们的细胞和分子后果,并测试它们对表型的影响, HTT突变在目标3中,我们将对LIG 1 K845 N进行生化、结构和功能分析。 变量。总之,这些实验将提供新的洞察机制,遗传变异, LIG 1修饰患者的疾病,最终揭示了可以用于疾病的治疗途径- 修改治疗方法。

项目成果

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Ihn Sik Seong其他文献

Ihn Sik Seong的其他文献

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{{ truncateString('Ihn Sik Seong', 18)}}的其他基金

An alternative isoform of RRM2B as a genetic modifier in Huntington's disease
RRM2B 的另一种亚型作为亨廷顿病的遗传修饰剂
  • 批准号:
    10405581
  • 财政年份:
    2020
  • 资助金额:
    $ 63.07万
  • 项目类别:
An Alternative Isoform of RRM2B as a Genetic Modifier in Huntington's Disease
RRM2B 的替代亚型作为亨廷顿病的遗传修饰剂
  • 批准号:
    10621765
  • 财政年份:
    2020
  • 资助金额:
    $ 63.07万
  • 项目类别:
Effects of PolyQ Expansion on Full-length Huntingtin Protein in HD
PolyQ 扩增对 HD 中全长亨廷顿蛋白的影响
  • 批准号:
    8343248
  • 财政年份:
    2012
  • 资助金额:
    $ 63.07万
  • 项目类别:
Effects of PolyQ Expansion on Full-length Huntingtin Protein in HD
PolyQ 扩增对 HD 中全长亨廷顿蛋白的影响
  • 批准号:
    8659524
  • 财政年份:
    2012
  • 资助金额:
    $ 63.07万
  • 项目类别:
Effects of PolyQ Expansion on Full-length Huntingtin Protein in HD
PolyQ 扩增对 HD 中全长亨廷顿蛋白的影响
  • 批准号:
    8487470
  • 财政年份:
    2012
  • 资助金额:
    $ 63.07万
  • 项目类别:
Effects of PolyQ Expansion on Full-length Huntingtin Protein in HD
PolyQ 扩增对 HD 中全长亨廷顿蛋白的影响
  • 批准号:
    8842213
  • 财政年份:
    2012
  • 资助金额:
    $ 63.07万
  • 项目类别:

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