Functional Assessment of Variants in Organisms of Research (FAVOR) - Profiling Canonical Human Genes and their Variants through Disease Model Phenotyping.

研究有机体变异的功能评估 (FAVOR) - 通过疾病模型表型分析典型人类基因及其变异。

基本信息

  • 批准号:
    10011229
  • 负责人:
  • 金额:
    $ 35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-05-01 至 2023-04-30
  • 项目状态:
    已结题

项目摘要

Project Summary / Abstract Genome wide DNA sequencing is now being adopted in clinical practice and an increasing number of variants are identified in epilepsy-associated genes, yet the clinical interpretation of the new variants is challenging. Some of the variants are known to be either pathological or benign, yet a majority of the gene variations remain unknown for their functional consequence. A large number of Variant of Uncertain Significance (VUS) are becoming commonplace in genes for human diseases, providing a significant barrier in making diagnoses and implementing therapies. Bioinformatic approaches can provide some insight into pathogenic probability of VUS alleles, but functional studies in animal model systems are often needed to make definitive of pathogenicity assignments. The expense and long timelines of mouse model production make the use of alternative small animal models attractive. In this proposal, the ​C. elegans​nematode is used as an alternative model capable of fast high-throughput production and screening. Human genes are installed as gene-swap replacements of the native disease-gene homologs. In preliminary work, gene-swap humanization of STXBP1 in the ​unc-18​locus rescued severe locomotion and behavior defects present in the gene knock-out animals. Pathogenic variants into the STXBP1​​gene-swap loci leads to significant disruption of activity. In this proposal, significant and novel improvements are made to our existing pipeline for the functional analysis of variants in vivo. In Aim 1, the relevance and extensibility of the C. elegans model system for studying human disease is improved through simultaneous humanization of multiple related loci. In Aim 2, new methods are developed for molecular phenotyping, improving the resolution of inputs pathogenicity determination algorithms, and yielding mechanism-of-action level readouts to variant manipulations. In Aim 3, the improvements to the pipeline are tested to quantify gains in pathogenicity determination on a test set of variants.
项目摘要/摘要

项目成果

期刊论文数量(0)
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Trisha Brock其他文献

Trisha Brock的其他文献

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{{ truncateString('Trisha Brock', 18)}}的其他基金

Improving Husbandry and Data Reproducibility Through Automated Health Monitoring in Zebrafish Facilities
通过斑马鱼设施的自动健康监测改善饲养和数据再现性
  • 批准号:
    10761190
  • 财政年份:
    2023
  • 资助金额:
    $ 35万
  • 项目类别:
DanFreez: Zebrafish Genetically-Optimized for Cryogenic Storage of Embryos
DanFreez:针对胚胎低温储存进行基因优化的斑马鱼
  • 批准号:
    10385461
  • 财政年份:
    2022
  • 资助金额:
    $ 35万
  • 项目类别:
Administrative Supplement: Functional Assessment of Variants in Organisms of Research (FAVOR) - Profiling Canonical Human Genes and their Variants through Disease Model Phenotyping.
行政补充:研究有机体变异的功能评估(FAVOR)——通过疾病模型表型分析典型人类基因及其变异。
  • 批准号:
    10228504
  • 财政年份:
    2020
  • 资助金额:
    $ 35万
  • 项目类别:
A fluorescent reporter detecting precise homologous recombination transgenesis activity
检测精确同源重组转基因活性的荧光报告基因
  • 批准号:
    9520355
  • 财政年份:
    2017
  • 资助金额:
    $ 35万
  • 项目类别:
A fluorescent reporter detecting precise homologous recombination transgenesis activity
检测精确同源重组转基因活性的荧光报告基因
  • 批准号:
    9456176
  • 财政年份:
    2017
  • 资助金额:
    $ 35万
  • 项目类别:
A fluorescent reporter detecting precise homologous recombination transgenesis activity
检测精确同源重组转基因活性的荧光报告基因
  • 批准号:
    9255240
  • 财政年份:
    2016
  • 资助金额:
    $ 35万
  • 项目类别:

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