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:10432743
- 负责人:
- 金额:$ 42.24万
- 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/摘要
唐氏综合征(DS)是智力残疾最常见的遗传原因。几十年来,我们都知道
第21号染色体(Hsa 21)的额外拷贝导致了广泛的生理和
与DS相关的发育表型。然而,我们远远落后于解决两个关键问题,
DS研究中的问题:1)哪些Hsa 21基因在DS中过表达时引起表型,以及
相反,2)哪些Hsa 21基因可能被靶向以改善DS的表型。研究人员使用鼠标
模型已经发现,少数Hsa 21基因在某些表型中起作用,
过表达,如阿尔茨海默病(APP)和白血病(GATA 1)。绝大多数Hsa 21
然而,由于研究Hsa 21上超过200个基因是不切实际的,因此没有详细研究基因。
使用小鼠模型研究每个Hsa 21基因是耗时且昂贵的。相反,我们建议
系统地研究单个Hsa 21基因直系同源物使用的有效模式秀丽隐杆线虫。
最近,我们发现,除了48个角蛋白基因,C。秀丽线虫有超过一半的剩余Hsa 21的直系同源物
基因,其中51个是高度保守的。通过对51个同源基因的突变和RNAi分析,我们发现,
14个是必需基因,10个是神经和/或肌肉功能所必需的,其中3个基因没有表达。
以前被研究过。为了探讨单个Hsa 21基因的过表达(OE)如何有助于
与DS相关的表型,我们将实现互补的目标。对于目标1,我们将系统地测试
在51个直系同源物中,一个接一个地引起OE表型。对于目标2,使用转基因蠕虫,携带额外的
所有51个Hsa 21同源基因的拷贝,我们将系统地测试哪些Hsa 21同源基因可能被敲除
降低OE表型。对于我们能够通过基因敲除抑制的OE表型,我们将
还研究了潜在的细胞分子机制基础,
C.优美的我们的项目将利用尖端的转基因和基因敲除工具,以及采取
我们实验室在高通量定量表型分析方面的专业知识优势。通过鉴定Hsa 21基因,
在C. elegans,这项研究将聚焦基因,以优先考虑进一步
使用小鼠和人类干细胞模型的DS研究。将共享产生的Hsa 21 OE菌株集
自由地在世界各地建立C。秀丽线虫作为第一个方便研究的体内机制模型
Hsa 21基因过表达的后果。从这项研究中获得的见解将突出新颖且
作为改善DS患者健康的潜在治疗靶点。
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:
$ 42.24万 - 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:
10651500 - 财政年份:2022
- 资助金额:
$ 42.24万 - 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:
$ 42.24万 - 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:
$ 42.24万 - 项目类别:
ANALYSIS OF MOTOR PATTERN SWITCHING BY DOPAMINE
多巴胺对运动模式切换的分析
- 批准号:
8291979 - 财政年份:2011
- 资助金额:
$ 42.24万 - 项目类别:
ANALYSIS OF MOTOR PATTERN SWITCHING BY DOPAMINE
多巴胺对运动模式切换的分析
- 批准号:
8478221 - 财政年份:2011
- 资助金额:
$ 42.24万 - 项目类别:
ANALYSIS OF MOTOR PATTERN SWITCHING BY DOPAMINE
多巴胺对运动模式切换的分析
- 批准号:
8162634 - 财政年份:2011
- 资助金额:
$ 42.24万 - 项目类别:
ANALYSIS OF MOTOR PATTERN SWITCHING BY DOPAMINE
多巴胺对运动模式切换的分析
- 批准号:
8846149 - 财政年份:2011
- 资助金额:
$ 42.24万 - 项目类别:
ANALYSIS OF MOTOR PATTERN SWITCHING BY DOPAMINE
多巴胺对运动模式切换的分析
- 批准号:
8664453 - 财政年份:2011
- 资助金额:
$ 42.24万 - 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:
$ 42.24万 - 项目类别: