The role of cGAS in Senesence and the formation of SADS
cGAS 在衰老和 SADS 形成中的作用
基本信息
- 批准号:10231400
- 负责人:
- 金额:$ 4.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAgeAgingAnti-Inflammatory AgentsAttenuatedBiochemistryBiology of AgingCell AgingCell Cycle ArrestCell NucleusCellsCellular StressCellular biologyCentromereChIP-seqCharacteristicsChromatinChronicCyclic GMPCytosolDNADNA DamageDNA RepairDataDementiaDepositionDeteriorationDiabetes MellitusDiploidyElementsEnsureEventExtracellular Matrix ProteinsFellowshipFibroblastsGenetic TranscriptionGenomeGenomicsGoalsGrowth FactorHealthHumanImageImmuneInfectionInflammationInflammation MediatorsInflammatoryInternationalKnock-outKnowledgeLabelLaboratory ResearchLeadLongevityLungMaintenanceMalignant NeoplasmsMeasuresMediatingMentorsMicroscopyMolecularMolecular BiologyNuclearPathologyPhenotypePlayPoint MutationPreparationProcessProliferatingPublishingRecruitment ActivityRepetitive SequenceReportingResearchResearch TrainingResolutionRisk FactorsRoleShapesSignal TransductionSignaling MoleculeSiteStressStructureTechnologyTestingTimeTrainingUniversitiesWorkage relatedanti agingbiological adaptation to stressbody systemcareercell injurychemokinechronic inflammatory diseasecollaborative environmentcytokineenvironmental stressorexperiencehealthspanhomologous recombinationimprovedin situ sequencinginhibitor/antagonistinsightmicrobialnovel therapeutic interventionnucleasepreventprogramsrecombinational repairrecruitresponsesenescencesensorskillssuccesssupportive environmentsymposiumtool
项目摘要
Project Summary
Aging is characterized by a general decline in overall health and a gradual deterioration across multiple
organ systems. However, our understanding of the aging process and whether we can improve health span
remains a topic of active research. One of the hallmarks of aging is cellular senescence, a stress response that
limits the propagation of damaged cells by causing irreversible cell cycle arrest. The DNA damage response is
one of the key events leading to senescence. Cells in early senescence show increased satellite transcription
and centromere instability and dysmorphism, known as the senescence-associated distension of satellites
(SADS). Cyclic GMP-AMP synthase (cGAS) is a cytosolic innate immune sensor that recognizes and responds
to microbial and self-DNA. Cytoplasmic cGAS is essential for the establishment of senescence and the secretion
of inflammatory mediators characteristic of senescence. However, little is known of cGAS deposition and function
in the nucleus. Nuclear cGAS has been reported to inhibit the DNA Damage Response (DDR) via homologous
recombination (HR) in the nucleus and to be enriched at repetitive sequences such as centromeres and long
interspersed nuclear element (LINE) DNA repeats. Despite these recent findings, the question remains whether
cGAS contributes to senescence entry by modulating HR repair and whether cGAS concentration at centromeres
and LINEs plays a role in the formation of SADS in early senescence. To answer these questions, I propose the
following two aims: Aim 1 will determine whether cGAS inhibition of the DDR contributes to cell entry into
senescence. Aim 2 will determine whether cGAS plays a role in SADS formation in senescence. The findings of
this project will provide mechanistic insight on the effect of nuclear cGAS in the DDR and centromere stability,
and its role in the establishment of senescence. Advancing our knowledge of nuclear cGAS can further current
efforts to develop inhibitors of cGAS as potential anti-inflammatory or anti-aging therapy as strategies that extend
healthy lifespan.
This proposal will be the first to examine the relationship between nuclear cGAS and senescence using
cutting edge technology in imaging and unique expertise in its influence at repetitive elements. One of this
fellowship's training goals is to develop the repertoire of skills and body of knowledge for a successful career in
the biology of aging research. The second goal is to gain experience in effectively communicating research in a
variety of settings. To achieve these goals, completion of the proposed research, attending the Gordon Research
Conference, presenting at national and international conferences, and my sponsor's mentoring will ensure the
success of this training plan. Furthermore, this proposal will take place in the excellent environment of the
interdisciplinary and supportive Molecular Biology, Cell Biology, and Biochemistry program at Brown University.
Completion of this research and training plan will move the biology of aging field forward and provide me with
the ideal preparation towards the career goal of leading an independent academic research laboratory.
项目概要
老龄化的特点是整体健康状况普遍下降,多个方面逐渐恶化。
器官系统。然而,我们对衰老过程的了解以及我们是否可以改善健康寿命
仍然是一个活跃的研究课题。衰老的标志之一是细胞衰老,这是一种应激反应,
通过引起不可逆的细胞周期停滞来限制受损细胞的增殖。 DNA损伤反应是
导致衰老的关键事件之一。早期衰老细胞显示卫星转录增加
着丝粒不稳定和畸形,称为衰老相关卫星扩张
(SADS)。环 GMP-AMP 合酶 (cGAS) 是一种胞质先天免疫传感器,可识别并做出反应
微生物和自身 DNA。细胞质 cGAS 对于衰老的建立和分泌至关重要
衰老特征的炎症介质。然而,人们对 cGAS 的沉积和功能知之甚少
在细胞核中。据报道,核 cGAS 可通过同源酶抑制 DNA 损伤反应 (DDR)
重组(HR)在细胞核中,并在重复序列(例如着丝粒和长序列)处富集
散布的核元件 (LINE) DNA 重复序列。尽管有这些最近的发现,问题仍然是:
cGAS 通过调节 HR 修复以及着丝粒处的 cGAS 浓度来促进衰老进入
LINEs在衰老早期SADS的形成中发挥作用。为了回答这些问题,我建议
以下两个目标:目标 1 将确定 DDR 的 cGAS 抑制是否有助于细胞进入
衰老。目标 2 将确定 cGAS 是否在衰老过程中 SADS 的形成中发挥作用。调查结果
该项目将为核 cGAS 对 DDR 和着丝粒稳定性的影响提供机制见解,
及其在衰老过程中的作用。提高我们对核 cGAS 的了解可以进一步推动当前
努力开发 cGAS 抑制剂作为潜在的抗炎或抗衰老疗法,作为延长治疗时间的策略
健康的寿命。
该提案将是第一个利用核 cGAS 和衰老之间的关系进行研究的提案
尖端的成像技术和独特的专业知识对重复元素的影响。其中之一
奖学金的培训目标是发展技能和知识体系,以实现成功的职业生涯
衰老研究的生物学。第二个目标是获得有效交流研究的经验
各种设置。为了实现这些目标,完成拟议的研究,参加戈登研究
会议、在国内和国际会议上发表演讲以及我的赞助商的指导将确保
本次培训计划的成功。此外,本提案将在良好的环境下进行
布朗大学的跨学科和支持性分子生物学、细胞生物学和生物化学项目。
这项研究和培训计划的完成将推动衰老领域的生物学向前发展,并为我提供
为领导独立学术研究实验室的职业目标做好理想的准备。
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 }}
Azucena V Rocha其他文献
Azucena V Rocha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('Azucena V Rocha', 18)}}的其他基金
The role of cGAS in Senesence and the formation of SADS
cGAS 在衰老和 SADS 形成中的作用
- 批准号:
10682506 - 财政年份:2021
- 资助金额:
$ 4.6万 - 项目类别:
The role of cGAS in Senesence and the formation of SADS
cGAS 在衰老和 SADS 形成中的作用
- 批准号:
10533726 - 财政年份:2021
- 资助金额:
$ 4.6万 - 项目类别:
相似国自然基金
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
- 批准号:JCZRQN202500010
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
- 批准号:2025JJ70209
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
- 批准号:
- 批准年份:2024
- 资助金额:0 万元
- 项目类别:面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
- 批准号:2023JJ50274
- 批准年份:2023
- 资助金额:0.0 万元
- 项目类别:省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
- 批准号:
- 批准年份:2022
- 资助金额:33 万元
- 项目类别:地区科学基金项目
补肾健脾祛瘀方调控AGE/RAGE信号通路在再生障碍性贫血骨髓间充质干细胞功能受损的作用与机制研究
- 批准号:
- 批准年份:2022
- 资助金额:52 万元
- 项目类别:面上项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
- 批准号:n/a
- 批准年份:2022
- 资助金额:10.0 万元
- 项目类别:省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
- 批准号:81973577
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
- 批准号:81602908
- 批准年份:2016
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
- 批准号:81501928
- 批准年份:2015
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
相似海外基金
The Phenomenon of Stem Cell Aging according to Methylation Estimates of Age After Hematopoietic Stem Cell Transplantation
根据造血干细胞移植后甲基化年龄估算干细胞衰老现象
- 批准号:
23K07844 - 财政年份:2023
- 资助金额:
$ 4.6万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Analysis of Age-dependent Functional Changes in Skeletal Muscle CB1 Receptors by an in Vitro Model of Aging-related Muscle Atrophy
通过衰老相关性肌肉萎缩的体外模型分析骨骼肌 CB1 受体的年龄依赖性功能变化
- 批准号:
22KJ2960 - 财政年份:2023
- 资助金额:
$ 4.6万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Joint U.S.-Japan Measures for Aging and Dementia Derived from the Prevention of Age-Related and Noise-induced Hearing Loss
美日针对预防与年龄相关和噪声引起的听力损失而导致的老龄化和痴呆症联合措施
- 批准号:
23KK0156 - 财政年份:2023
- 资助金额:
$ 4.6万 - 项目类别:
Fund for the Promotion of Joint International Research (International Collaborative Research)
The Effects of Muscle Fatigability on Gait Instability in Aging and Age-Related Falls Risk
肌肉疲劳对衰老步态不稳定性和年龄相关跌倒风险的影响
- 批准号:
10677409 - 财政年份:2023
- 资助金额:
$ 4.6万 - 项目类别:
Characterizing gut physiology by age, frailty, and sex: assessing the role of the aging gut in "inflamm-aging"
按年龄、虚弱和性别表征肠道生理学特征:评估衰老肠道在“炎症衰老”中的作用
- 批准号:
497927 - 财政年份:2023
- 资助金额:
$ 4.6万 - 项目类别:
Deciphering the role of osteopontin in the aging eye and age-related macular degeneration
破译骨桥蛋白在眼睛老化和年龄相关性黄斑变性中的作用
- 批准号:
10679287 - 财政年份:2023
- 资助金额:
$ 4.6万 - 项目类别:
Role of AGE/RAGEsignaling as a driver of pathological aging in the brain
AGE/RAGE信号传导作为大脑病理性衰老驱动因素的作用
- 批准号:
10836835 - 财政年份:2023
- 资助金额:
$ 4.6万 - 项目类别:
Elucidation of the protein kinase NLK-mediated aging mechanisms and treatment of age-related diseases
阐明蛋白激酶NLK介导的衰老机制及年龄相关疾病的治疗
- 批准号:
23K06378 - 财政年份:2023
- 资助金额:
$ 4.6万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Underlying mechanisms of age-related changes in ingestive behaviors: From the perspective of the aging brain and deterioration of the gustatory system.
与年龄相关的摄入行为变化的潜在机制:从大脑老化和味觉系统退化的角度来看。
- 批准号:
23K10845 - 财政年份:2023
- 资助金额:
$ 4.6万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Targeting Age-Activated Proinflammatory Chemokine Signaling by CCL2/11 to Enhance Skeletal Muscle Regeneration in Aging
通过 CCL2/11 靶向年龄激活的促炎趋化因子信号传导以增强衰老过程中的骨骼肌再生
- 批准号:
478877 - 财政年份:2023
- 资助金额:
$ 4.6万 - 项目类别:
Operating Grants