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

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.
项目摘要/摘要 唐氏综合症(DS)是导致智力残疾的最常见的遗传原因。几十年来,我们都知道 21号染色体的一个额外拷贝(Hsa21)导致了广泛的生理和 与DS相关的发育表型。然而,我们在解决两个关键问题上远远落后 DS研究中的问题:1)在DS中过度表达时,哪些Hsa21基因会导致表型,以及 相反,哪些Hsa21基因可能是DS表型改善的靶点。研究人员使用鼠标 模型已经发现少数几个Hsa21基因在某些表型中扮演的角色 过度表达,如阿尔茨海默病(APP)和白血病(GATA1)。绝大多数HSA21 然而,由于研究Hsa21上的200多个基因是不切实际的,因此还没有对基因进行详细的研究。 用小鼠模型研究每一种Hsa21基因既耗时又昂贵。相反,我们建议 利用高效的秀丽线虫模型对个体Hsa21基因同源序列进行系统研究。 最近,我们发现,不包括48个角蛋白基因,线虫在剩余的Hsa21中有超过一半的同源基因 基因,其中51个高度保守。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个没有 以前已经研究过了。探索单个Hsa21基因的过度表达(OE)是如何导致 对于与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个同源基因中,一个接一个地导致OE表型。对于目标2,使用携带额外基因的转基因蠕虫 所有51个Hsa21同源基因的拷贝,我们将系统地测试哪些Hsa21同源基因可能被敲除 以减少OE表型。对于我们能够通过基因敲除而抑制的OE表型,我们将 还可以使用独特的便捷方法研究潜在的细胞-分子机制基础 线虫。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 利用我们实验室在高通量定量表型鉴定方面的专业知识。通过鉴定Hsa21基因 在线虫中过度表达会导致表型,这项研究将重点关注基因,以便进一步确定优先顺序 使用小鼠和人类干细胞模型研究DS。生产的一套Hsa21 OE菌株将被共享 在世界各地自由建立线虫作为第一个便于研究的机械性活体模型 Hsa21基因过度表达的后果。从这项研究中获得的见解将突出新奇和 未确定的分子通路作为改善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)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

JONATHAN THOMAS PIERCE其他文献

JONATHAN THOMAS PIERCE的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:
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:
    $ 6.62万
  • 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:
    $ 6.62万
  • 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:
    $ 6.62万
  • 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:
    $ 6.62万
  • 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:
    $ 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:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了