Investigating cysteine-mediated protein activities in C. elegans

研究线虫中半胱氨酸介导的蛋白质活性

基本信息

  • 批准号:
    9119183
  • 负责人:
  • 金额:
    $ 36.43万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-08-03 至 2020-05-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): The molecular mechanisms underlying the aging process are poorly understood, thereby hindering the development of therapeutics to delay the onset of aging and age-related degenerative diseases. Genetic studies in the widely used model organism, Caenorhabditis elegans, have generated daf-2 mutants defective in insulin/IGF-1 signaling (IIS), which have significantly extended lifespans. The daf-2 mutation activates DAF-16, a transcription factor, which initiates downstream gene expression changes that mediate the life-extension phenotype. We have identified protein-activity changes that are downstream effects of DAF-16 activation using the tools of chemical proteomics. These studies complement conventional genomic and proteomic approaches by providing insight into low-abundance proteins and posttranslational modifications (PTMs) implicated in IIS. From our preliminary studies, we identified a lipid-binding protein, LBP-3, which upon RNAi-mediated knockdown increases both lifespan and dauer formation in C. elegans. Given the established dysregulation of lipid metabolism in IIS, and the confirmed role of other lipid-binding proteins in controlling lifespan and stress resistance, we hypothesize that LBP-3 is a novel mediator of IIS. To test this hypothesis, we will determine the mechanism by which LBP-3 acts within known nodes of the IIS pathway to regulate lifespan. Furthermore, since mammalian homologs of LBP-3 are known to be redox regulated, and dysregulation of reactive oxygen species (ROS) levels is a characteristic feature of IIS, we will investigate the in vivo oxidation state of LBP-3. In additio to revealing a novel mode of regulation for C. elegans LBP-3, these studies will also serve to more globally evaluate protein oxidation events accompanying IIS. Lastly, since oxidation of mammalian LBPs is known to affect protein stability and lipid binding, we will evaluate the effect of oxidation on C. elegans LBP-3 function. LBP-3 contains a highly reactive cysteine residue, Cys154, which is the predicted site of oxidation. We will exploit this reactive cysteine to develop covalent small-molecule probes and inhibitors to pharmacologically modulate LBP-3 function in C. elegans. Together, these studies will: (1) characterize a novel downstream mediator of C. elegans IIS; (2) reveal the role of protein oxidation in governing the function of LBP-3 and other C. elegans proteins during IIS; and (3) demonstrate that LBP-3 can be targeted by small molecules to pharmacologically modulate C. elegans lifespan.
 描述(申请人提供):衰老过程背后的分子机制知之甚少,因此阻碍了延缓衰老和与年龄相关的退行性疾病的治疗方法的发展。在广泛使用的模式生物秀丽线虫的遗传学研究中,已经产生了胰岛素/胰岛素样生长因子-1信号(IIS)缺陷的daf-2突变体,这些突变体显著延长了寿命。Daf-2突变激活了转录因子DAF-16,从而启动了下游基因表达的变化,从而介导了寿命延长的表型。我们已经利用化学蛋白质组学的工具确定了DAF-16激活的下游影响的蛋白质活性变化。这些研究通过深入了解IIS中涉及的低丰度蛋白质和翻译后修饰(PTM),补充了传统的基因组和蛋白质组方法。从我们的初步研究中,我们确定了一种脂结合蛋白LBP-3,它在RNAi介导的击倒后延长了线虫的寿命和Dauer的形成。鉴于IIS中已证实的脂代谢失调,以及其他脂结合蛋白在控制寿命和应激抗性方面的已证实作用,我们假设LBP-3是IIS的一个新的介体。为了验证这一假说,我们将确定LBP-3在IIS途径的已知节点内发挥作用以调节寿命的机制。此外,由于LBP-3的哺乳动物同源物是已知的氧化还原调节的,而活性氧物种(ROS)水平的失调是IIS的特征,因此我们将研究LBP-3在体内的氧化状态。除了揭示线虫LBP-3的一种新的调控模式外,这些研究还将有助于更全面地评估伴随IIS的蛋白质氧化事件。最后,由于哺乳动物LBPS的氧化已知会影响蛋白质的稳定性和脂质结合,我们将评估氧化对线虫LBP-3功能的影响。LBP-3含有一个高活性的半胱氨酸残基,Cys154,这是预测的氧化位点。我们将利用这种反应性半胱氨酸来开发 药物调节线虫LBP-3功能的共价小分子探针和抑制剂。综上所述,这些研究将:(1)表征线虫IIS的一个新的下游介体;(2)揭示在IIS过程中蛋白质氧化在调节LBP-3和其他线虫蛋白功能中的作用;以及(3)证明LBP-3可以被小分子靶向,从药物上调节线虫的寿命。

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 }}

Eranthie Weerapana其他文献

Eranthie Weerapana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('Eranthie Weerapana', 18)}}的其他基金

Developing chemical-proteomic tools to investigate cysteine oxidation
开发化学蛋白质组学工具来研究半胱氨酸氧化
  • 批准号:
    10551830
  • 财政年份:
    2020
  • 资助金额:
    $ 36.43万
  • 项目类别:
Developing chemical-proteomic tools to investigate cysteine oxidation
开发化学蛋白质组学工具来研究半胱氨酸氧化
  • 批准号:
    10318977
  • 财政年份:
    2020
  • 资助金额:
    $ 36.43万
  • 项目类别:
Developing chemical-proteomic tools to investigate cysteine oxidation
开发化学蛋白质组学工具来研究半胱氨酸氧化
  • 批准号:
    10077867
  • 财政年份:
    2020
  • 资助金额:
    $ 36.43万
  • 项目类别:

相似海外基金

Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
  • 批准号:
    MR/S03398X/2
  • 财政年份:
    2024
  • 资助金额:
    $ 36.43万
  • 项目类别:
    Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
  • 批准号:
    2338423
  • 财政年份:
    2024
  • 资助金额:
    $ 36.43万
  • 项目类别:
    Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
  • 批准号:
    EP/Y001486/1
  • 财政年份:
    2024
  • 资助金额:
    $ 36.43万
  • 项目类别:
    Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
  • 批准号:
    MR/X03657X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 36.43万
  • 项目类别:
    Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
  • 批准号:
    2348066
  • 财政年份:
    2024
  • 资助金额:
    $ 36.43万
  • 项目类别:
    Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
  • 批准号:
    AH/Z505481/1
  • 财政年份:
    2024
  • 资助金额:
    $ 36.43万
  • 项目类别:
    Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10107647
  • 财政年份:
    2024
  • 资助金额:
    $ 36.43万
  • 项目类别:
    EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
  • 批准号:
    2341402
  • 财政年份:
    2024
  • 资助金额:
    $ 36.43万
  • 项目类别:
    Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
  • 批准号:
    10106221
  • 财政年份:
    2024
  • 资助金额:
    $ 36.43万
  • 项目类别:
    EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
  • 批准号:
    AH/Z505341/1
  • 财政年份:
    2024
  • 资助金额:
    $ 36.43万
  • 项目类别:
    Research Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了