Dissecting the role of reproduction in regulating lysosomal function in C. elegans

剖析线虫繁殖在调节溶酶体功能中的作用

基本信息

  • 批准号:
    RGPIN-2018-03751
  • 负责人:
  • 金额:
    $ 2.62万
  • 依托单位:
  • 依托单位国家:
    加拿大
  • 项目类别:
    Discovery Grants Program - Individual
  • 财政年份:
    2019
  • 资助国家:
    加拿大
  • 起止时间:
    2019-01-01 至 2020-12-31
  • 项目状态:
    已结题

项目摘要

Reproduction and aging are linked processes in eukaryotes. Across different species, aging is synchronized with the reproductive cycle such that progeny generation coincides with the time when the animal is the fittest. Mutations in C. elegans that prevent germ cell proliferation also increase longevity, pointing to a genetically regulated cross talk between the gonad and the soma to influence fitness. How this cross-tissue signaling functions during the reproductive cycle, and through which cellular processes it acts in somatic cells, remains unclear. My research group is studying the molecular underpinning of the synchrony between reproduction and somatic fitness. We have recently identified a functional link between reproduction and lysosomal pH in somatic cells that provides a plausible model to explain how C. elegans integrates signals from the gonad to delay aging via improved proteolysis: in animals that have ceased reproduction, lysosomal-mediated proteolysis in the soma collapses and tissue deterioration ensues. The overarching goal of this research is to understand the genetic mechanisms that connect life history traits, such as reproduction and aging. Specifically, the proposed research aims to dissect the genes necessary to regulate lysosomal function, and consequently protein homeostasis, as animals age. In Objective 1, we will extend our efforts to isolate and characterize the genes required to trigger gonad-to-soma signaling at the transition between reproductive and non-reproductive periods through genome-wide genetic screens. We will use our expertise in developing transgenic sensors and pH-sensitive assays to detect dynamic changes in lysosomal pH in intestine and muscle of live worms as a phenotypic readout for these experiments. In Objective 2, we will address the chemical composition of intestinal cells that are influenced by signaling from the gonad following the end of reproduction. We will take a spectroscopic approach to quantitatively measure endogenous changes in the molecular signatures of live intestinal cells using Fourier-Transform Infrared Spectroscopy (FTIR) analysis. This work will take advantage of our previous experience in Mid-IR imaging of live C. elegans oocytes at the Canadian Light Source (CLS) and is expected to generate a detailed chemical map of aging-associated markers. Finally, in Objective 3, we will investigate the specific impact of lysosomal function in aging by using transgenic interventions to control lysosomal pH, followed by lifespan analyses. To this end, we will use transgenic and optogenetic tools that allow for in vivo vesicle acidification. In summary, these experiments will reveal novel genes that integrate reproductive information to modulate aging. Considering the evolutionary conservation of aging networks, we expect this research to be relevant to vertebrate systems as well.
繁殖和衰老是真核生物中相互联系的过程。在不同的物种中,衰老与生殖周期同步,使得后代的产生与动物最适者生存的时间相一致。C.突变秀丽隐杆线虫能阻止生殖细胞增殖,也能延长寿命,这表明生殖腺和索马之间的基因调控相互作用影响了健康。这种跨组织信号在生殖周期中如何发挥作用,以及它在体细胞中通过哪些细胞过程起作用,目前尚不清楚。我的研究小组正在研究生殖和身体健康之间同步的分子基础。我们最近发现了体细胞中生殖和溶酶体pH之间的功能联系,这为解释C。秀丽隐杆线虫整合来自性腺的信号,通过改善的蛋白水解延缓衰老:在停止繁殖的动物中,索马体中的溶酶体介导的蛋白水解崩溃,组织退化加剧。这项研究的首要目标是了解连接生活史特征的遗传机制,如生殖和衰老。具体来说,拟议中的研究旨在解剖调节溶酶体功能所必需的基因,从而随着动物年龄的增长保持蛋白质稳态。在目标1中,我们将通过全基因组遗传筛选来分离和表征在生殖期和非生殖期之间的过渡期触发性腺到索马信号传导所需的基因。我们将利用我们在开发转基因传感器和pH敏感性测定方面的专业知识,检测活蠕虫肠道和肌肉中溶酶体pH的动态变化,作为这些实验的表型读数。在目标2中,我们将讨论生殖结束后受性腺信号影响的肠细胞的化学组成。我们将采用光谱方法,使用傅立叶变换红外光谱(FTIR)分析定量测量活肠细胞分子特征的内源性变化。这项工作将利用我们以前的经验,在中红外成像的活C。elegans卵母细胞在加拿大光源(CLS),并预计产生一个详细的化学图谱的老化相关的标志物。最后,在目标3中,我们将通过使用转基因干预来控制溶酶体pH值,然后进行寿命分析,研究溶酶体功能在衰老中的具体影响。为此,我们将使用允许体内囊泡酸化的转基因和光遗传学工具。总之,这些实验将揭示整合生殖信息以调节衰老的新基因。考虑到老化网络的进化保守性,我们希望这项研究也与脊椎动物系统相关。

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 }}

EgydioDeCarvalho, Carlos其他文献

EgydioDeCarvalho, Carlos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 }}

相似国自然基金

PfAP2-R介导的PfCRT转录调控在恶性疟原虫对喹啉类药物抗性中的作用及机制研究
  • 批准号:
    82372275
  • 批准年份:
    2023
  • 资助金额:
    49.00 万元
  • 项目类别:
    面上项目
Sestrin2抑制内质网应激对早产儿视网膜病变的调控作用及其机制研究
  • 批准号:
    82371070
  • 批准年份:
    2023
  • 资助金额:
    49.00 万元
  • 项目类别:
    面上项目

相似海外基金

Dissecting a hormone-responsive processor for female activity and repetitive behavior
剖析女性活动和重复行为的激素反应处理器
  • 批准号:
    10796627
  • 财政年份:
    2023
  • 资助金额:
    $ 2.62万
  • 项目类别:
Dissecting cryptic genetic variation underlying complex traits in Drosophila
剖析果蝇复杂性状背后的神秘遗传变异
  • 批准号:
    10796086
  • 财政年份:
    2023
  • 资助金额:
    $ 2.62万
  • 项目类别:
Dissecting the role of RPLP1 in female reproductive tract pathologies
剖析 RPLP1 在女性生殖道病理中的作用
  • 批准号:
    10508848
  • 财政年份:
    2022
  • 资助金额:
    $ 2.62万
  • 项目类别:
Dissecting the role of RPLP1 in female reproductive tract pathologies
剖析 RPLP1 在女性生殖道病理中的作用
  • 批准号:
    10705087
  • 财政年份:
    2022
  • 资助金额:
    $ 2.62万
  • 项目类别:
Develop enabling biochemical and structural tools for dissecting the roles of PKD2L2 in metabolism
开发有利的生化和结构工具来剖析 PKD2L2 在代谢中的作用
  • 批准号:
    10452211
  • 财政年份:
    2022
  • 资助金额:
    $ 2.62万
  • 项目类别:
Dissecting the role of reproduction in regulating lysosomal function in C. elegans
剖析线虫繁殖在调节溶酶体功能中的作用
  • 批准号:
    RGPIN-2018-03751
  • 财政年份:
    2021
  • 资助金额:
    $ 2.62万
  • 项目类别:
    Discovery Grants Program - Individual
Dissecting a hormone-responsive processor for female activity and repetitive behavior
剖析女性活动和重复行为的激素反应处理器
  • 批准号:
    10578739
  • 财政年份:
    2020
  • 资助金额:
    $ 2.62万
  • 项目类别:
Dissecting a hormone-responsive processor for female activity and repetitive behavior
剖析女性活动和重复行为的激素反应处理器
  • 批准号:
    10115716
  • 财政年份:
    2020
  • 资助金额:
    $ 2.62万
  • 项目类别:
Dissecting the role of reproduction in regulating lysosomal function in C. elegans
剖析线虫繁殖在调节溶酶体功能中的作用
  • 批准号:
    RGPIN-2018-03751
  • 财政年份:
    2020
  • 资助金额:
    $ 2.62万
  • 项目类别:
    Discovery Grants Program - Individual
Dissecting a hormone-responsive processor for female activity and repetitive behavior
剖析女性活动和重复行为的激素反应处理器
  • 批准号:
    10361212
  • 财政年份:
    2020
  • 资助金额:
    $ 2.62万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了