Coordination of PAR and Ub signaling in mitochondria
线粒体中 PAR 和 Ub 信号传导的协调
基本信息
- 批准号:10623889
- 负责人:
- 金额:$ 43.14万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2028-03-31
- 项目状态:未结题
- 来源:
- 关键词:ADP ribosylationAddressAreaCell DeathCell NucleusCommunicationComplementDedicationsDepartment of DefenseDiseaseEnzymesEukaryotic CellFutureGPS2 geneGene Expression RegulationGenetic TranscriptionGenome StabilityGenomicsHomeostasisInnate Immune ResponseLinkMediatingMetabolicMetabolic ControlMetabolic PathwayMitochondriaMitochondrial ProteinsMolecularNational Institute of Diabetes and Digestive and Kidney DiseasesNational Institute of General Medical SciencesNatural ImmunityNuclearNutrient availabilityObesityOrganellesOxidative StressPathway interactionsPhysiologicalPlayPositioning AttributePost-Translational Protein ProcessingProcessProductionRegulationResearchRoleSignal TransductionStressTherapeuticTransferaseTranslational RegulationTranslationsUbiquitinUbiquitinationWorkbiological adaptation to stressinhibitorinsightmalignant breast neoplasmprogramsresponsetargeted treatmenttranslational potential
项目摘要
Project Summary/Abstract
Over the past 10 years, our research program has aimed at discovering molecular mechanisms that control
metabolic adaptation in response to nutrient availability, cellular differentiation, and oxidative stress through
genomic reprogramming. With NIGMS support, we have made significant contributions to identifying
mechanisms responsible for the coordinated regulation of gene transcription and translation during the
Mitochondrial Stress Response (MSR). Our work has identified a key role for non-degradative ubiquitination in
both processes, showing that the regulated shuttling of GPS2 – an endogenous inhibitor of K63 ubiquitination –
between mitochondria and nucleus is an essential strategy for maintaining mitochondrial homeostasis. As a
complement to these mechanistic studies, we also investigated – in projects supported by NIDDK and the
Department of Defense – the physiological relevance and translational potential GPS2-mediated regulation of
ubiquitin signaling in breast cancer and obesity-associated disorders. Together, these studies have revealed the
importance of GPS2-mediated restriction of K63Ub signaling in promoting metabolic adaptation and
mitochondria remodeling during stress and cellular differentiation. This large body of work highlights our
expertise in the field and our unique position to further investigate the crosstalk between this newly identified
pathway and other PTMs involved in regulating mitochondrial function. In particular, we will focus our future
studies on the crosstalk between ubiquitination and ADP-ribosylation. These PTMs work in tandem in the
regulation of nuclear genome stability, innate immunity and stress-induced translational regulation. However,
their relationship in regulating mitochondrial function has not yet been investigated. In fact, although the presence
of ADP-ribosylation activity in mitochondria was known for decades, the identity of the mitochondrial ART
enzyme/s has been elusive, hindering more detailed studies on the role and regulation of mitochondrial proteins
through ADP-ribosylation. As we recently identified NEURL4 as a mitochondria-dedicated ADP-ribosyl
transferase under the regulation of stress-induced and GPS2-mediated reprogramming, we are now in the
position of carrying those studies. We propose a research plan spanning two major areas:1) Investigating the
spatial and functional regulation of mitochondria retrograde signaling in response to mitochondrial stress and 2)
Exploring the crosstalk between ubiquitination and ADP-ribosylation in regulating mitochondrial homeostasis.
Our research plan addresses three key problems: i) the spatial regulation of mitochondria retrograde signaling;
ii) the functional contribution of mitochondria retrograde signaling to the regulation of ADP-ribosylation and
ubiquitination across subcellular compartments; iii) the molecular mechanisms underlying the coordinated
regulation of ADP-ribosylation/ ubiquitination. Successful completion of the proposed studies will lead to a better
understanding of the mechanisms regulating mitochondria homeostasis through post-translational modifications
and possibly reveal regulatory strategies to be targeted for therapeutic purposes.
项目摘要/摘要
在过去的10年里,我们的研究计划旨在发现控制
代谢适应对营养供应、细胞分化和氧化应激的反应
基因组重编程。在NIGMS的支持下,我们在识别
负责协调调节基因转录和翻译的机制
线粒体应激反应(MSR)。我们的工作已经确定了非降解性泛素化在
这两个过程都表明,K63泛素化的内源性抑制物GPS2的调节穿梭-
线粒体与细胞核之间的相互作用是维持线粒体动态平衡的基本策略。作为一名
作为对这些机制研究的补充,我们还调查了由NIDDK和
国防部-GPS2介导的生理相关性和翻译潜能调节
泛素信号在乳腺癌和肥胖相关疾病中的作用。总之,这些研究揭示了
GPS2介导的抑制K63Ub信号通路在促进代谢适应中的重要性
应激和细胞分化过程中线粒体的重塑。这一大堆工作突出了我们的
在该领域的专业知识和我们的独特地位,以进一步调查之间的串扰新发现
途径和其他参与调节线粒体功能的PTM。特别是,我们将把我们的未来放在
泛素化和adp-核糖化之间的串扰研究。这些PTM在
核基因组稳定性的调节、先天免疫和应激诱导的翻译调节。然而,
它们在调节线粒体功能方面的关系尚未得到研究。事实上,尽管出现了
线粒体中ADP核糖化活性的研究几十年来一直是已知的,这是线粒体ART的相同之处
酶/S一直难以捉摸,阻碍了对线粒体蛋白的作用和调控的更详细研究
通过ADP-核糖化。因为我们最近鉴定出NEURL4是线粒体专属的ADP-核糖基
在应激诱导和GPS2介导的重编程的调节下,我们现在处于
承担这些研究的职位。我们提出了一个涵盖两个主要领域的研究计划:1)调查
线粒体应激反应中线粒体逆行信号的空间和功能调节
探讨泛素化和ADP核糖化在调节线粒体动态平衡中的相互作用。
我们的研究计划解决了三个关键问题:i)线粒体逆行信号的空间调控;
Ii)线粒体逆行信号对ADP-核糖化调节的功能贡献和
跨亚细胞隔间的泛素化;iii)协调的
ADP-核糖化/泛素化的调节。成功完成拟议的研究将带来更好的
翻译后修饰调控线粒体动态平衡的机制
并可能揭示针对治疗目的的调控策略。
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 }}
VALENTINA PERISSI其他文献
VALENTINA PERISSI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('VALENTINA PERISSI', 18)}}的其他基金
Regulation of mitochondrial homeostasis through retrograde signaling
通过逆行信号调节线粒体稳态
- 批准号:
9924614 - 财政年份:2018
- 资助金额:
$ 43.14万 - 项目类别:
Regulation of mitochondrial homeostasis through retrograde signaling
通过逆行信号调节线粒体稳态
- 批准号:
10133090 - 财政年份:2018
- 资助金额:
$ 43.14万 - 项目类别:
Ubiquitin-dependent regulation of inflammation and insulin resistance
炎症和胰岛素抵抗的泛素依赖性调节
- 批准号:
9243244 - 财政年份:2014
- 资助金额:
$ 43.14万 - 项目类别:
Ubiquitin-dependent regulation of inflammation and insulin resistance
炎症和胰岛素抵抗的泛素依赖性调节
- 批准号:
9040938 - 财政年份:2014
- 资助金额:
$ 43.14万 - 项目类别:
Role of the NCoR corepressor complex in the development of insulin resistance
NCoR 辅阻遏物复合物在胰岛素抵抗发展中的作用
- 批准号:
8149970 - 财政年份:2010
- 资助金额:
$ 43.14万 - 项目类别:
Role of the NCoR corepressor complex in the development of insulin resistance
NCoR 辅阻遏物复合物在胰岛素抵抗发展中的作用
- 批准号:
8328959 - 财政年份:2010
- 资助金额:
$ 43.14万 - 项目类别:
Role of the NCoR corepressor complex in the development of insulin resistance
NCoR 辅阻遏物复合物在胰岛素抵抗发展中的作用
- 批准号:
8138837 - 财政年份:2010
- 资助金额:
$ 43.14万 - 项目类别:
Role of the NCoR corepressor complex in the development of insulin resistance
NCoR 辅阻遏物复合物在胰岛素抵抗发展中的作用
- 批准号:
7300065 - 财政年份:2007
- 资助金额:
$ 43.14万 - 项目类别:
Role of the NCoR corepressor complex in the development of insulin resistance
NCoR 辅阻遏物复合物在胰岛素抵抗发展中的作用
- 批准号:
7456334 - 财政年份:2007
- 资助金额:
$ 43.14万 - 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:
$ 43.14万 - 项目类别:
Fellowship
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:
$ 43.14万 - 项目类别:
Research Grant
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:
$ 43.14万 - 项目类别:
Continuing 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:
$ 43.14万 - 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:
$ 43.14万 - 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:
$ 43.14万 - 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:
$ 43.14万 - 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:
$ 43.14万 - 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:
$ 43.14万 - 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:
$ 43.14万 - 项目类别:
Research Grant














{{item.name}}会员




