A cell model of YARS2-associated childhood-onset mitochondrial disease

YARS2 相关的儿童期发病线粒体疾病的细胞模型

基本信息

  • 批准号:
    10575369
  • 负责人:
  • 金额:
    $ 8.99万
  • 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:
    2023-02-01 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY We hypothesize that pathogenic variants in the family of the nuclear ARS2 genes, encoding mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs), cause disease primarily by disrupting nutrient sensing and cell signaling. Each mt-aaRS is responsible for charging its cognate mitochondrial tRNA (mt-tRNA) with its specific amino acid, as required for the dedicated mitochondrial protein synthesis machinery. Loss-of-function variants of each ARS2 have been linked to human diseases, showing central nervous system involvement, myopathy, sensorineural hearing loss, ovarian dysgenesis, and pulmonary hypertension. However, the correlation is poor between the enzymatic activity of individual variants and manifestation of the disease phenotypes. This suggests that disease is mediated not necessarily via loss of tRNA charging, but by other functions of mt-aaRSs. Given that the cytosolic counterpart ARS1 genes are often implicated in non-canonical functions, beyond aminoacylation, we will test the hypothesis that ARS2s mediate nutrient-sensing and cell-signaling processes that are disrupted by pathogenic variants resulting in disease development. To test this hypothesis, as a pilot model, we will generate a human subject-derived induced pluripotent stem cell (iPSC) line with pathogenic variants in the YARS2 gene, encoding mt-TyrRS. Pathogenic variants of YARS2 result in the MLASA (myopathy, lactic acidosis and sideroblastic anemia) syndrome. Previous studies of pathogenic YARS2 variants have shown no appreciable effect on tRNA aminoacylation. Here we focus on a pair of novel compound heterozygous mutations that we identified in a human subject with neonatal fatal disease, the most severe clinical case observed to date. This provides a unique model where the largest changes in nutrient sensing and cell signaling are expected to occur. In Aim 1, we will create an iPSC line from an established fibroblast line of the human subject. We will use CRISPR/Cas to generate an isogenic control line that corrects the genetic mutations. In Aim 2, we will differentiate the patient and control iPSC lines to disease-relevant cell types. We will focus on myocytes, as skeletal myopathy is the most notable feature of clinical cases of YARS2 variants. We will also focus on peripheral neurons, which are affected in most clinical cases of other ARS2 variants. We will identify changes of gene expression in nutrient sensing or cell signaling of the subject line. Combined, this work will produce an isogenic pair of subject and control iPSC lines that will be shared with the research community. This pair of iPSC lines will serve as the foundation for understanding the implications of nutrient sensing and cell signaling in YARS2 variants, which will provide a template that is generalizable to other ARS2-associated disease.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Ya-Ming Hou其他文献

Ya-Ming Hou的其他文献

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{{ truncateString('Ya-Ming Hou', 18)}}的其他基金

The tRNA pool in C9-ALS/FTD
C9-ALS/FTD 中的 tRNA 池
  • 批准号:
    10662716
  • 财政年份:
    2023
  • 资助金额:
    $ 8.99万
  • 项目类别:
TrmD-targeting actinobacterial natural products as next generation antibiotics
TrmD靶向放线菌天然产物作为下一代抗生素
  • 批准号:
    10307014
  • 财政年份:
    2021
  • 资助金额:
    $ 8.99万
  • 项目类别:
TrmD-targeting actinobacterial natural products as next generation antibiotics
TrmD靶向放线菌天然产物作为下一代抗生素
  • 批准号:
    10625857
  • 财政年份:
    2021
  • 资助金额:
    $ 8.99万
  • 项目类别:
TrmD-targeting actinobacterial natural products as next generation antibiotics
TrmD靶向放线菌天然产物作为下一代抗生素
  • 批准号:
    10438880
  • 财政年份:
    2021
  • 资助金额:
    $ 8.99万
  • 项目类别:
tRNA in codon usage
密码子使用中的 tRNA
  • 批准号:
    10581912
  • 财政年份:
    2020
  • 资助金额:
    $ 8.99万
  • 项目类别:
Exploring 3Dpol for RNA sequencing in real time
探索 3Dpol 实时 RNA 测序
  • 批准号:
    10166895
  • 财政年份:
    2020
  • 资助金额:
    $ 8.99万
  • 项目类别:
Exploring 3Dpol for RNA sequencing in real time
探索 3Dpol 实时 RNA 测序
  • 批准号:
    9974889
  • 财政年份:
    2020
  • 资助金额:
    $ 8.99万
  • 项目类别:
tRNA in codon usage
密码子使用中的 tRNA
  • 批准号:
    10116428
  • 财政年份:
    2020
  • 资助金额:
    $ 8.99万
  • 项目类别:
tRNA in codon usage
密码子使用中的 tRNA
  • 批准号:
    10371216
  • 财政年份:
    2020
  • 资助金额:
    $ 8.99万
  • 项目类别:
tRNA in codon usage
密码子使用中的 tRNA
  • 批准号:
    10576809
  • 财政年份:
    2020
  • 资助金额:
    $ 8.99万
  • 项目类别:

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