The methyltransferase Smyd1 regulates cardiac physiology
甲基转移酶 Smyd1 调节心脏生理学
基本信息
- 批准号:10522980
- 负责人:
- 金额:$ 40.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-15 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AdultArteriesBindingBlood flowCardiacCardiac MyocytesCause of DeathCellsChIP-seqClinicalClustered Regularly Interspaced Short Palindromic RepeatsComplexCongestive Heart FailureCoronary ArteriosclerosisCrista ampullarisDataDiseaseDown-RegulationElectron MicroscopyElectron TransportEpigenetic ProcessEventExhibitsFluorometryGene ExpressionGenesGenetic TranscriptionHealthHeart failureHistone DeacetylaseHistone-Lysine N-MethyltransferaseHistonesHumanHypertrophic CardiomyopathyIschemiaKnockout MiceMediatingMetabolismMethylationMethyltransferaseMitochondriaMolecularMorphologyMusMuscle CellsMutationMyocardial IschemiaMyocardial dysfunctionMyocardiumOPA1 geneOrthologous GenePathogenicityPathologicPathway interactionsPatientsPhysiologyPrevention therapyProductionProtein IsoformsProtonsPublishingRegulationReperfusion TherapyResolutionRespirationRespiratory ChainRoleStructureTertiary Protein StructureTestingTherapeuticTherapeutic InterventionTissuesTranscriptTransgenic MiceVarianteffective therapygain of functiongenome-wideheart metabolismhuman diseasehuman tissuein vivoinduced pluripotent stem cellinsightischemic injuryloss of functionmouse modelmyocardial injurynoveloverexpressionpreventpromoterprotein expressiontherapeutic target
项目摘要
PROJECT SUMMARY
Coronary artery disease is the leading cause of death in the US and is the primary cause of chronic heart failure.
For patients with coronary artery disease, some advancements have been made clinically to restore blood flow
in diseased arteries and reduce myocardial injury from the resulting ischemia and subsequent reperfusion.
However, even with these advancements one quarter of patients will die or develop heart failure within 1 year.
Damage to the myocardium during ischemic injury includes deficiencies in metabolism and energetics. Some
key epigenetic regulators can prevent or reduce ischemic injury and pathological remodeling in murine models,
however, their ubiquitous expression has made them unsuitable for therapeutic targeting in humans, thus far. In
contrast, we recently identified the only known myocyte-specific epigenetic regulator of mitochondrial energetics
and metabolism – the histone lysine methyltransferase Smyd1 – which holds great therapeutic potential given
its tissue-specific expression. Specifically, we performed the first analysis of Smyd1 function in the adult
myocardium using inducible, cardiomyocyte-specific Smyd1 knockout mice and showed that loss of Smyd1 leads
to dysregulated cardiac metabolism and suppressed mitochondrial respiration, ultimately leading to heart failure
(published in AJP). Subsequently we showed that down-regulation of mitochondrial energetics is an early event
in these knockout mice (occurring before the onset of cardiac dysfunction) and results, at least in part, from
Smyd1’s regulation of PGC-1α transcription (published in PNAS). To further understand Smyd1’s role in
regulating cardiac physiology we recently generated transgenic mice allowing inducible, cardiomyocyte-specific
overexpression of the Smyd1a isoform (the mouse ortholog to human SMYD1) and subjected these mice to
permanent occlusion of the LAD. Our unpublished preliminary results show that Smyd1a gain-of-function can
enhance mitochondrial respiration and protect from ischemic injury, although how this is accomplished
molecularly is unknown. In addition, our preliminary data from these mice show increased mitochondrial cristae
formation and stabilization of respiratory chain supercomplexes within the cristae, concomitant with increased
Opa1 expression, a known driver of cristae morphology. These results implicate Opa1 as a novel, functionally
important downstream target of Smyd1a whereby cardiomyocytes upregulate energy efficiency, protecting them
from ischemic injury. Our overarching hypothesis is that Smyd1a protects from ischemic injury by regulating
mitochondrial energetics and enhancing respiration efficiency in the cardiomyocyte through regulation of both:
1) PGC-1α expression (a regulator of electron transport chain gene expression) and 2) OPA1-mediated cristae
remodeling and stabilization of electron transport chain supercomplexes. We will test this hypothesis in our
transgenic mice which conditionally overexpress Smyd1a. In addition, we will examine these pathways in cells
and human tissue with a putative SMYD1 loss-of-function variant, N101S, which we identified with collaborators
at the U. of Pittsburgh (Dr Lina Gonzalez) in a patient with hypertrophic cardiomyopathy and heart failure.
项目摘要
冠状动脉疾病是美国死亡的主要原因,是慢性心力衰竭的主要原因。
对于冠状动脉疾病的患者,已经在临床上取得了一些进步以恢复血流
在解散的动脉中,减少了由此产生的缺血和随后再灌注的心肌损伤。
但是,即使有这些进步,有四分之一的患者也会在1年内死亡或发展心力衰竭。
缺血性损伤期间心肌的损害包括代谢和能量学的缺陷。一些
关键的表观遗传调节剂可以预防或减少鼠模型中的缺血性损伤和病理重塑,
但是,到目前为止,它们无处不在的表达使它们不适合人类的治疗靶向。
对比,我们最近确定了线粒体能量的唯一已知的肌细胞特异性表观遗传调节剂
和代谢 - 组蛋白赖氨酸甲基转移酶SMYD1 - 具有巨大的治疗潜力
它的组织特异性表达。具体而言,我们对成人进行了SMYD1功能的首次分析
使用诱导的,心肌细胞特异性SMYD1敲除小鼠的心肌,表明SMYD1铅的损失
使心脏代谢失调并抑制线粒体呼吸,最终导致心力衰竭
(发表在AJP中)。随后,我们表明线粒体能量的下调是早期事件
在这些敲除小鼠中(发生在心脏功能障碍发作之前),至少部分是从
SMYD1对PGC-1α转录的调节(在PNA中发表)。进一步了解smyd1在
调节心脏生理学我们最近产生的转基因小鼠允许诱导,心肌细胞特异性小鼠
Smyd1a同工型的过表达(小鼠与人smyd1的直系同源物),并将这些小鼠进行
小伙子的永久阻塞。我们未发表的初步结果表明,smyd1a功能奖可以
增强线粒体呼吸并防止缺血性损伤,尽管如何实现
分子是未知的。此外,我们来自这些小鼠的初步数据显示线粒体cristae增加
Cristae内呼吸链超复合物的形成和稳定,随之增加
OPA1表达,是Cristae形态的已知驱动力。这些结果暗示OPA1是一种小说,在功能上
Smyd1a的重要下游靶标,在该目标中,心肌细胞上调能源效率,保护它们
因缺血性损伤。我们的总体假设是SMYD1A通过调节来保护缺血性损伤
线粒体能量学和通过调节心肌细胞增强呼吸效率:
1)PGC-1α表达(电子传输链基因表达的调节剂)和2)OPA1介导的Cristae
电子传输链超复合物的重塑和稳定。我们将在我们的
有条件过表达Smyd1a的转基因小鼠。此外,我们将检查细胞中的这些途径
和具有推定的SMYD1功能丧失变体N101S的人体组织,我们与合作者一起确定
在匹兹堡大学(Lina Gonzalez博士),患有肥厚性心肌病和心力衰竭的患者。
项目成果
期刊论文数量(0)
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Sarah Franklin其他文献
Sarah Franklin的其他文献
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{{ truncateString('Sarah Franklin', 18)}}的其他基金
The methyltransferase Smyd1 regulates cardiac physiology
甲基转移酶 Smyd1 调节心脏生理学
- 批准号:
10666617 - 财政年份:2022
- 资助金额:
$ 40.04万 - 项目类别:
Regulation of cardiac hypertrophy and failure by the histone methyltransferase Smyd1
组蛋白甲基转移酶 Smyd1 对心脏肥大和衰竭的调节
- 批准号:
9198054 - 财政年份:2016
- 资助金额:
$ 40.04万 - 项目类别:
Reprogramming of cardiac genome by Smyd1 in hypertrophy and failure
Smyd1 在肥厚和衰竭中对心脏基因组进行重编程
- 批准号:
8723268 - 财政年份:2011
- 资助金额:
$ 40.04万 - 项目类别:
Reprogramming of cardiac genome by Smyd1 in hypertrophy and failure
Smyd1 在肥厚和衰竭中对心脏基因组进行重编程
- 批准号:
8528045 - 财政年份:2011
- 资助金额:
$ 40.04万 - 项目类别:
Reprogramming of cardiac genome by Smyd1 in hypertrophy and failure
Smyd1 在肥厚和衰竭中对心脏基因组进行重编程
- 批准号:
8092249 - 财政年份:2011
- 资助金额:
$ 40.04万 - 项目类别:
Reprogramming of cardiac genome by Smyd1 in hypertrophy and failure
Smyd1 在肥厚和衰竭中对心脏基因组进行重编程
- 批准号:
8535191 - 财政年份:2011
- 资助金额:
$ 40.04万 - 项目类别:
Reprogramming of cardiac genome by Smyd1 in hypertrophy and failure
Smyd1 在肥厚和衰竭中对心脏基因组进行重编程
- 批准号:
8249849 - 财政年份:2011
- 资助金额:
$ 40.04万 - 项目类别:
Bmx Tyrosine Kinase Signaling in Cardiac Protection
Bmx 酪氨酸激酶信号传导在心脏保护中的作用
- 批准号:
7408825 - 财政年份:2008
- 资助金额:
$ 40.04万 - 项目类别:
Bmx Tyrosine Kinase Signaling in Cardiac Protection
Bmx 酪氨酸激酶信号传导在心脏保护中的作用
- 批准号:
7779514 - 财政年份:2008
- 资助金额:
$ 40.04万 - 项目类别:
Bmx Tyrosine Kinase Signaling in Cardiac Protection
Bmx 酪氨酸激酶信号传导在心脏保护中的作用
- 批准号:
7581041 - 财政年份:2008
- 资助金额:
$ 40.04万 - 项目类别:
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