Activation of sirtuins to prevent adverse cardiac remodeling after CABG
激活sirtuins以预防CABG后不良心脏重塑
基本信息
- 批准号:8620707
- 负责人:
- 金额:$ 38.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-02-15 至 2017-01-31
- 项目状态:已结题
- 来源:
- 关键词:AbdomenAdultAgonistAnimal ModelAnimalsAntioxidantsApoptosisBiochemicalBiologicalBiological ProcessCardiacCardiac MyocytesCardiomyopathiesCause of DeathCell DeathCell NucleusCongestive Heart FailureConnective TissueContractile ProteinsCoronary ArteriosclerosisCoronary Artery BypassCytoskeletonDefense MechanismsDepositionDevelopmentDiseaseEchocardiographyExtracellular MatrixExtracellular Matrix ProteinsFailureFibroblastsFibrosisFunctional disorderGenetic TranscriptionGeometryGoalsHeartHeart BlockHeart DiseasesHeart HypertrophyHeart failureHumanHypertrophyImplantIn VitroInfarctionInferiorInjuryIschemiaLaboratoriesLeft Ventricular RemodelingLigationLinkLongevityMagnetic Resonance ImagingMammalian CellMechanical StressMediatingModelingMolecular BiologyMusMyocardialMyocardial InfarctionMyocardiumMyofibroblastNatural regenerationOperative Surgical ProceduresOrganOutcomeOxidative StressPathologic ProcessesPatientsPlayProceduresProcessProductionProtein BiosynthesisProtein IsoformsProteinsPumpRattusRegulationRoleSignal TransductionSirtuinsSmooth Muscle Actin Staining MethodStimulusTestingTimeTissuesTransgenic MiceVentricular RemodelingWild Type MouseWorkbasecell growthheart functionin vivointerestinterstitialmanmangenew therapeutic targetnovel strategiesnovel therapeuticspreventpublic health relevanceresearch studyresponsetranslational medicinetreatment strategy
项目摘要
DESCRIPTION (provided by applicant): Congestive heart failure (HF) is one of the leading causes of death and complications worldwide. Even after complete revascularization by coronary artery bypass grafting (CABG) patients with MI (myocardial infarction) often develop adverse ventricular remodeling in the remote myocardium which generates complications leading to HF. Both human and animal studies have demonstrated that biochemical and mechanical stress on the heart leads to cardiac myocyte hypertrophy and cardiac fibroblasts (CF) differentiation to myofibroblasts (myoFB) which deposit extracellular matrix (ECM), leading to adverse ventricular remodeling. The underlying mechanism of CF transformation to myoFB is not yet fully understood. New approaches are needed to define the mechanism behind this pathological process, and to identify new therapeutic strategies to protect the heart from descending to failure post MI. My laboratory has specific interest in sirtuins, which are capable of activating intracellular anti-oxidant defense mechanisms and extending life-span of species. Recent work from my laboratory has identified one sirtuin isoform, SIRT3 as an endogenous negative regulator of cardiac hypertrophy. SIRT3-deficent mice develop cardiac hypertrophy associated with interstitial fibrosis, and transgenic mice with cardiac-specific over expression of
SIRT3 are protected from developing hypertrophy. We also found that SIRT3 (-/-) fibroblasts are highly permissive to myoFB transformation, but not the fibroblasts over expressed with SIRT3. Additional studies done with human hearts showed that SIRT3 levels are dramatically reduced in patients with ischemic cardiomyopathy, and over expression of SIRT3 blocks pro-fibrotic effects of Ang-II on human CF in vitro. Based on these findings we hypothesized that loss of SIRT3 may be a cause of CF transformation to myoFB, and thus by maintaining cellular SIRT3 levels CF differentiation to myoFB can be blocked, and heart could be protected from developing fibrosis and HF. To test this hypothesis we propose three specific aims: (1) Study the role of SIRT3 in regulating adult human CF transformation to myoFB and the maladaptive cardiac remodeling. (2) Determine underlying mechanisms through which SIRT3 blocks human CF proliferation and transformation. (3) Test whether SIRT3 activation can be used as a novel therapeutic strategy to block maladaptive LV remodeling following MI in an animal model. A successful outcome of these three aims will have major impact on our understanding of the disease process of ventricular remodeling, and that this may guide us to identify new therapeutic targets critical for translational medicine of HF.
描述(由申请人提供):充血性心力衰竭(HF)是全球死亡和并发症的主要原因之一。即使经过冠状动脉搭桥术(CABG)患有MI(心肌梗塞)患者的血运重建,也经常在远程心肌中出现不良心室重塑,从而产生并发症,从而导致HF。人类和动物研究都表明,对心脏的生化和机械应力会导致心肌细胞肥大和心脏成纤维细胞(CF)分化与肌纤维细胞(MyOFB)的分化,它们沉积了细胞外基质(ECM),导致不良的心室重置。 CF转换为MyOFB的基本机制尚未完全理解。需要采用新的方法来定义这种病理过程背后的机制,并确定保护心脏免于下降到MI后失败的新治疗策略。我的实验室对Sirtuins具有特定的兴趣,Sirtuins能够激活细胞内抗氧化剂防御机制并延长物种的寿命。我的实验室的最近工作确定了一种Sirtuin同工型,SIRT3是心脏肥大的内源性负调节剂。 SIRT3缺乏小鼠发展与间质纤维化相关的心脏肥大,而转基因小鼠具有心脏特异性
SIRT3受到保护,免受肥大的发展。我们还发现SIRT3( - / - )成纤维细胞对MyOFB转化具有很高的允许,但并非用SIRT3表达的成纤维细胞。人类心脏进行的其他研究表明,缺血性心肌病患者的SIRT3水平大大降低,并且SIRT3的表达过多地阻断了Ang-II对人类CF体外CF的纤维化作用。基于这些发现,我们假设SIRT3的丢失可能是CF转化为MyOFB的原因,因此,通过保持细胞SIRT3水平CF的差异可以阻止与MyOFB的分化,可以保护心脏免受纤维化和HF的发展。为了检验这一假设,我们提出了三个具体目的:(1)研究SIRT3在调节成人人类CF转化为MyOFB和适应不良的心脏重塑中的作用。 (2)确定SIRT3阻止人CF增殖和转化的潜在机制。 (3)测试SIRT3激活是否可以用作一种新型的治疗策略,以阻止动物模型中MI后的适应不良的LV重塑。这三个目标的成功结果将对我们对心室重塑疾病过程的理解产生重大影响,这可能指导我们确定对HF转化医学至关重要的新治疗靶标。
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 }}
MAHESH P GUPTA其他文献
MAHESH P GUPTA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('MAHESH P GUPTA', 18)}}的其他基金
Exploring roles of sirtuins in protecting diabetic hearts
探索去乙酰化酶在保护糖尿病心脏中的作用
- 批准号:
9973114 - 财政年份:2018
- 资助金额:
$ 38.71万 - 项目类别:
Improving post-surgery recovery of failing hearts by targeting cardiomyocyte senescence
通过靶向心肌细胞衰老来改善衰竭心脏的术后恢复
- 批准号:
10199774 - 财政年份:2018
- 资助金额:
$ 38.71万 - 项目类别:
Improving post-surgery recovery of failing hearts by targeting cardiomyocyte senescence
通过靶向心肌细胞衰老来改善衰竭心脏的术后恢复
- 批准号:
9753360 - 财政年份:2018
- 资助金额:
$ 38.71万 - 项目类别:
Improving post-surgery recovery of failing hearts by targeting cardiomyocyte senescence
通过靶向心肌细胞衰老来改善衰竭心脏的术后恢复
- 批准号:
9978930 - 财政年份:2018
- 资助金额:
$ 38.71万 - 项目类别:
Exploring roles of sirtuins in protecting diabetic hearts
探索去乙酰化酶在保护糖尿病心脏中的作用
- 批准号:
10214667 - 财政年份:2018
- 资助金额:
$ 38.71万 - 项目类别:
Activation of sirtuins to prevent adverse cardiac remodeling after CABG
激活sirtuins以预防CABG后不良心脏重塑
- 批准号:
8789384 - 财政年份:2013
- 资助金额:
$ 38.71万 - 项目类别:
Activation of sirtuins to prevent adverse cardiac remodeling after CABG
激活sirtuins以预防CABG后不良心脏重塑
- 批准号:
8440040 - 财政年份:2013
- 资助金额:
$ 38.71万 - 项目类别:
The Role of PARP-SIR2 Signaling in Heart Failure
PARP-SIR2 信号传导在心力衰竭中的作用
- 批准号:
7789492 - 财政年份:2007
- 资助金额:
$ 38.71万 - 项目类别:
相似国自然基金
成人型弥漫性胶质瘤患者语言功能可塑性研究
- 批准号:82303926
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
MRI融合多组学特征量化高级别成人型弥漫性脑胶质瘤免疫微环境并预测术后复发风险的研究
- 批准号:82302160
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
成人免疫性血小板减少症(ITP)中血小板因子4(PF4)通过调节CD4+T淋巴细胞糖酵解水平影响Th17/Treg平衡的病理机制研究
- 批准号:82370133
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:面上项目
SMC4/FoxO3a介导的CD38+HLA-DR+CD8+T细胞增殖在成人斯蒂尔病MAS发病中的作用研究
- 批准号:82302025
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
融合多源异构数据应用深度学习预测成人肺部感染病原体研究
- 批准号:82302311
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
相似海外基金
Modeling genetic contributions to biliary atresia
模拟遗传对胆道闭锁的影响
- 批准号:
10639240 - 财政年份:2023
- 资助金额:
$ 38.71万 - 项目类别:
Obesity complicating type 1 diabetes in young people: Physiology and Impact of GLP-1 analogue anti-obesity treatment on cardiometabolic risk factors
年轻人肥胖并发 1 型糖尿病:GLP-1 类似物抗肥胖治疗的生理学和对心脏代谢危险因素的影响
- 批准号:
10736906 - 财政年份:2023
- 资助金额:
$ 38.71万 - 项目类别:
Glucagon-Like Peptide-1 Receptor Agonist Treatment in Adult, Obesity-Related, Symptomatic Asthma
胰高血糖素样肽 1 受体激动剂治疗成人肥胖相关症状性哮喘
- 批准号:
10398799 - 财政年份:2021
- 资助金额:
$ 38.71万 - 项目类别:
Glucagon-Like Peptide-1 Receptor Agonist Treatment in Adult, Obesity-Related, Symptomatic Asthma
胰高血糖素样肽 1 受体激动剂治疗成人肥胖相关症状性哮喘
- 批准号:
10609049 - 财政年份:2021
- 资助金额:
$ 38.71万 - 项目类别:
Glucagon-Like Peptide-1 Receptor Agonist Treatment in Adult, Obesity-Related, Symptomatic Asthma
胰高血糖素样肽 1 受体激动剂治疗成人肥胖相关症状性哮喘
- 批准号:
10084583 - 财政年份:2021
- 资助金额:
$ 38.71万 - 项目类别: