Dissecting the role of disease-associated variants in the regulation of TMEM106B

剖析疾病相关变异在 TMEM106B 调节中的作用

基本信息

  • 批准号:
    8836222
  • 负责人:
  • 金额:
    $ 4.27万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-12-01 至 2016-11-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Frontotemporal lobar degeneration (FTLD) accounts for 10-20% of dementia cases in individuals under age 65, and is a fatal disease with no available treatments. Three single nucleotide polymorphisms (SNPs) at the TMEM106B locus have been associated with increased risk of FTLD-TDP, the most common neuropathological subtype of FTLD, by genome-wide association study (GWAS). The risk allele of the top GWAS SNP, rs1990622, has been associated with increased TMEM106B levels in patient brain and lymphoblastoid cell lines (LCLs), suggesting that risk allele carriers may be more susceptible to disease due to increased TMEM106B expression in one or more brain cell types. TMEM106B levels are also increased in FTLD-TDP brains compared to neurologically normal controls, further establishing the importance of TMEM106B expression in disease. Intriguingly, TMEM106B genotype and expression have also been linked to progranulin, an important secreted neurotrophic factor. Loss-of-function mutations in the progranulin gene (GRN) are a common cause of familial FTLD-TDP, and overexpression of TMEM106B in cell culture systems affects intra- and extracellular levels of progranulin. Furthermore, individuals with the risk allee of the TMEM106B SNP rs1990622 have decreased plasma progranulin levels. Therefore, the risk allele of TMEM106B may influence risk for disease through an effect of TMEM106B expression levels on progranulin. The goal of this proposal is to identify the precise molecular mechanisms responsible for the increased TMEM106B levels seen in risk allele carriers, in order to identify regulatory pathways that can be targeted to modulate TMEM106B levels. Based on the linkage disequilibrium structure at the TMEM106B locus and fine-mapping of the LCL eQTL signal, candidate genetic variants were prioritized based on likelihood of regulatory function as assessed by ENCODE experimental data. This comprehensive, unbiased prioritization of variants resulted in the identification of two top candidate SNPs located in a predicted insulator region, which displays haplotype-dependent enhancer-blocking activity in cell-based reporter construct assays. Two major aims based on this preliminary data are proposed: 1) Determine the role of this region in the regulation of TMEM106B by in vivo genome editing, and 2) Identify the SNP(s) responsible for the haplotype effect on insulator function, and the molecular mechanisms involved. Elucidation of the precise molecular mechanisms underlying the association of TMEM106B genotype with expression levels, and by extension, disease risk, will reveal upstream regulatory pathways that can be targeted to manipulate TMEM106B levels.
 描述(由申请人提供):额颞叶变性(FTLD)占65岁以下个体痴呆病例的10-20%,是一种致命疾病,无可用治疗方法。TMEM 106 B位点的三个单核苷酸多态性(SNP)与FTLD-TDP(FTLD最常见的神经病理亚型)的风险增加相关,通过全基因组关联研究(GWAS)。最高GWAS SNP rs 1990622的风险等位基因与患者脑和淋巴母细胞系(LCL)中TMEM 106 B水平增加相关,表明风险等位基因携带者可能更容易因一种或多种脑细胞类型中TMEM 106 B表达增加而患病。与神经学正常对照相比,FTLD-TDP脑中的TMEM 106 B水平也增加,进一步确立了TMEM 106 B表达在疾病中的重要性。有趣的是,TMEM 106 B基因型和表达也与颗粒蛋白前体(一种重要的分泌型神经营养因子)有关。颗粒蛋白前体基因(GRN)的功能丧失突变是家族性FTLD-TDP的常见原因,细胞培养系统中TMEM 106 B的过表达影响颗粒蛋白前体的细胞内和细胞外水平。此外,具有TMEM 106 B SNP rs 1990622的风险等位基因的个体具有降低的血浆颗粒蛋白前体水平。因此,TMEM 106 B的风险等位基因可能通过TMEM 106 B表达水平对颗粒蛋白前体的影响来影响疾病风险。该提案的目标是确定负责在风险等位基因携带者中观察到的TMEM 106 B水平增加的精确分子机制,以确定可以靶向调节TMEM 106 B水平的调节途径。基于TMEM 106 B基因座的连锁不平衡结构和LCL eQTL信号的精细定位,基于ENCODE实验数据评估的调节功能的可能性对候选遗传变体进行优先排序。这种全面的、无偏的变体优先排序导致鉴定了位于预测绝缘子区域中的两个最佳候选SNP,其在基于细胞的报告构建体测定中显示单倍型依赖性增强子阻断活性。基于该初步数据提出了两个主要目标:1)通过体内基因组编辑确定该区域在TMEM 106 B调节中的作用,以及2)鉴定负责绝缘子功能的单倍型效应的SNP,以及 所涉及的分子机制。阐明TMEM 106 B基因型与表达水平相关的精确分子机制,并通过扩展,揭示疾病风险,将揭示可以靶向操纵TMEM 106 B水平的上游调控途径。

项目成果

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Michael D Gallagher其他文献

Michael D Gallagher的其他文献

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{{ truncateString('Michael D Gallagher', 18)}}的其他基金

Human induced pluripotent stem cell modeling of genetic risk factors for Alzheimer's disease
阿尔茨海默病遗传危险因素的人类诱导多能干细胞模型
  • 批准号:
    9762551
  • 财政年份:
    2019
  • 资助金额:
    $ 4.27万
  • 项目类别:
Human induced pluripotent stem cell modeling of genetic risk factors for Alzheimer's disease
阿尔茨海默病遗传危险因素的人类诱导多能干细胞模型
  • 批准号:
    10084218
  • 财政年份:
    2019
  • 资助金额:
    $ 4.27万
  • 项目类别:

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