Systematic functional study of 21st chromosome ortholog overexpression in C. elegans
线虫第 21 号染色体直系同源物过表达的系统功能研究
基本信息
- 批准号:10651500
- 负责人:
- 金额:$ 6.62万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAlzheimer&aposs DiseaseAlzheimer&aposs disease pathologyAnimal ModelApoptosisBehavioralBiological AssayCaenorhabditis elegansCharacteristicsChildhoodChromosome abnormalityChromosomesClustered Regularly Interspaced Short Palindromic RepeatsCodeConsumptionDefectDevelopmentDown SyndromeEarly Onset Alzheimer DiseaseEpilepsyEssential GenesEtiologyFrequenciesGATA1 geneGene DosageGenesGeneticHealthHumanIndividualInheritedIntellectual functioning disabilityKnock-inLeadLettersMAP Kinase GeneMethaqualoneModelingMolecularMusMuscleMuscle functionMutateNatural regenerationNematodaNerve DegenerationNervous system structureNeuronsOrthologous GenePathway interactionsPersonsPhenotypePhysiologicalPhysiologyPlayProcessProteinsRNA InterferenceResearchResearch PersonnelRiskRoleSYNJ1 geneSeriesSeveritiesSleep disturbancesSpeedSynapsesTestingTimeTransgenic Organismsaxon guidancebasebehavioral studycholinergiccholinergic neuroncongenital heart disordercostdosagehuman stem cellsimprovedin vivoin vivo Modelinduced pluripotent stem cellinnovationinsightknock-downleukemiamotor disordermouse modelmutantneurobehavioralnovelnovel therapeuticsoverexpressionpartial trisomy 21relating to nervous systemscreeningstem cell modeltheoriestherapeutic targettool
项目摘要
PROJECT SUMMARY/ABSTRACT
Down syndrome (DS) is the most common genetic cause of intellectual disability. For decades, we have known
that an extra copy of the 21st chromosome (Hsa21) causes the broad array of physiological and
developmental phenotypes associated with DS. However, we are far behind on addressing two critical
questions in DS research: 1) Which Hsa21 genes cause phenotypes when overexpressed in DS, and
conversely, 2) Which Hsa21 genes might be targeted to improve phenotypes in DS. Researchers using mouse
models have discovered the role that a handful of Hsa21 genes play in certain phenotypes when
overexpressed, such as Alzheimer’s pathology (APP) and leukemia (GATA1). The vast majority of Hsa21
genes, however, have not been studied in detail due to the impracticality of studying over 200 genes on Hsa21.
Studying each of the Hsa21 genes using mouse models is time-consuming and costly. Instead, we propose to
systematically study individual Hsa21 gene orthologs using the efficient model Caenorhabditis elegans.
Recently, we found that, excluding 48 keratin genes, C. elegans has orthologs for over half of remaining Hsa21
genes, 51 of which are highly-conserved. Through mutant and RNAi analysis of the 51 orthologs, we found that
14 are essential genes and 10 are required for neural and/or muscular function, three of which had not
previously been studied. To probe how overexpression (OE) of individual Hsa21 genes contributes to
phenotypes relevant to DS, we will carry out complementary aims. For Aim 1, we will systematically test which
of the 51 orthologs cause OE phenotypes one-by-one. For Aim 2, using a transgenic worm that carries extra
copies of all 51 Hsa21 orthologs, we will systematically test which of the Hsa21 orthologs may be knocked
down to reduce OE phenotypes. For OE phenotypes that we are able to suppress by gene knock down, we will
also investigate the underlying cellular-molecular mechanistic bases with convenient approaches unique to
C. elegans. Our project will leverage cutting-edge transgenic and gene knockdown tools, as well as take
advantage of our lab’s expertise in high-throughput quantitative phenotyping. By identifying Hsa21 genes that
cause phenotypes when overexpressed in C. elegans, this study will spotlight genes to prioritize for further
study using mouse and human stem-cell models of DS. The set of Hsa21 OE strains produced will be shared
freely around the world to establish C. elegans as the first mechanistic in vivo model to conveniently study
consequences of Hsa21 gene overexpression. Insights gained from this study will highlight novel and
uncharacterized molecular pathways as potential therapeutic targets for improving health in those with DS.
项目总结/文摘
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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JONATHAN THOMAS PIERCE其他文献
JONATHAN THOMAS PIERCE的其他文献
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{{ truncateString('JONATHAN THOMAS PIERCE', 18)}}的其他基金
High-throughput interrogation of autism risk genes: from molecules to behavior
自闭症风险基因的高通量询问:从分子到行为
- 批准号:
10639807 - 财政年份:2023
- 资助金额:
$ 6.62万 - 项目类别:
Systematic functional study of 21st chromosome ortholog overexpression in C. elegans
线虫第 21 号染色体直系同源物过表达的系统功能研究
- 批准号:
10841755 - 财政年份:2022
- 资助金额:
$ 6.62万 - 项目类别:
Systematic functional study of 21st chromosome ortholog overexpression in C. elegans
线虫第 21 号染色体直系同源物过表达的系统功能研究
- 批准号:
10432743 - 财政年份:2022
- 资助金额:
$ 6.62万 - 项目类别:
Synergistic patterned neurodegeneration by APP and APOE4
APP 和 APOE4 的协同模式神经变性
- 批准号:
9414391 - 财政年份:2017
- 资助金额:
$ 6.62万 - 项目类别:
Adaptive tissue permeability to alcohol in C. elegans
线虫对酒精的适应性组织渗透性
- 批准号:
8064549 - 财政年份:2010
- 资助金额:
$ 6.62万 - 项目类别:














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