Lysine Acetyltransferase 6A in Health and Cardiac Diseases
赖氨酸乙酰转移酶 6A 在健康和心脏病中的作用
基本信息
- 批准号:10442359
- 负责人:
- 金额:$ 39.25万
- 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:2021-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:AcetylationAcetyltransferaseAddressAnabolismAttenuatedBindingBiological AssayBiological ProcessCaloriesCarbohydratesCardiacCardiac MyocytesCell NucleusClinicalDietDietary ComponentEpigenetic ProcessFastingFatty AcidsFutureGene DeliveryGenomicsGlucoseGoalsHealthHeartHeart DiseasesHeart HypertrophyHeart failureHistonesHomeostasisHumanHydroxybutyratesHypertrophyIn VitroIntakeInterventionKetone BodiesKnock-in MouseLifeLigationLysineMammalsMediatingMolecularMolecular ConformationMorphologyMusMyocardialNutrientOral IngestionOxygen ConsumptionPathologicPathologyPathway interactionsPatientsPharmacologic ActionsPharmacologyPhenylephrinePhosphorylationPost-Translational Protein ProcessingPrimary PreventionProductionProtein BiosynthesisProteomicsRegulationResistanceRoleSecondary PreventionSignal TransductionSourceSystemTestingTherapeuticUp-Regulationbasecardioprotectiondeprivationexperimental studyheart functionimprovedin vivomTOR inhibitionmutantnovelnovel therapeutic interventionoxidationpressureprotein protein interactionresponsetherapeutic targettreatment strategy
项目摘要
PROJECT SUMMARY
Pathological hypertrophy can progress to failing heart. During the transition, fatty acid utilization is decreased,
while utilization of other substrates, such as ketone body, is increased. Multiple lines of evidence indicate that
increased myocardial ketone body utilization is an adaptive response against cardiac pathology. Furthermore,
although ketoacidosis is life-threatening, short-term administration of exogenous ketone body enhances
myocardial oxygen consumption with increases in both ketone body oxidation and overall ATP production in
the heart. This intervention improves cardiac function and remodeling in humans and mice with heart failure
(HF). Although ketone body serves as not only a fuel source but a modulator of lysine acetylation, the effect of
ketone body-mediated acetylation against hypertrophy and HF remains poorly understood. Elucidating the
molecular mechanisms of ketone body action beyond fueling, which mediates anti-hypertrophic and pro-
energetic effects without provoking detrimental effects, is the most important issue in establishing ketone body
as a therapeutic option for HF. We recently found that lysine acetyltransferase 6A (KAT6A) is acetylated in the
heart by a low-carbohydrate (LC) diet-mediated increase in ketone body, which is negatively associated with
hypertrophy and HF after pressure overload. Thus, we here ask whether acetylation of KAT6A is critically
involved in ketone body action against cardiac pathology. Our study provided evidence that acetylation of
KAT6A inhibits phenylephrine-induced hypertrophy and improves energy homeostasis in cardiomyocytes in
vitro. However, it remains unknown how KAT6A acetylation regulates cardiac morphology and function. Based
on these exciting observations we propose a novel role of KAT6A acetylation in pathological hypertrophy and
its transition to HF. Together with the surprising findings from our studies using proteomics and genomics
analyses, we hypothesize that ketone body promotes acetylation of KAT6A, which stimulates the AMPK
signaling in the heart to suppress protein synthesis and maintain energy homeostasis, thereby inhibiting
pathological hypertrophy and a transition to HF. To address this hypothesis, we will conduct the following
experiments. In Aim 1, we will determine the significance of KAT6A acetylation in pressure overload-induced
hypertrophy and HF in vivo by using newly generated KAT6A acetylation-resistant knock-in mice and an AAV-
KAT6A acetylation-mimicking mutant. In Aim 2, we will demonstrate the critical involvement of AMPK in KAT6A
action by pharmacologically and genetically inhibiting AMPK. We will further elucidate the mechanism by which
AMPK is activated by KAT6A by using molecular signaling and biological assays. The long-term goal of this
project is to identify the therapeutic targets to specifically modulate the ketone body-KAT6A-AMPK pathway
relevant to the strategies for the primary and secondary prevention of cardiac hypertrophy and HF.
项目概要
病理性肥大可进展为心脏衰竭。在转变过程中,脂肪酸的利用率降低,
同时增加了其他底物(例如酮体)的利用率。多项证据表明
心肌酮体利用率增加是针对心脏病理学的适应性反应。此外,
虽然酮症酸中毒危及生命,但短期给予外源性酮体可增强
心肌耗氧量随着酮体氧化和总 ATP 产生的增加而增加
心脏。这种干预措施可改善患有心力衰竭的人类和小鼠的心脏功能和重塑
(高频)。虽然酮体不仅是一种燃料来源,而且是赖氨酸乙酰化的调节剂,但酮体的作用
酮体介导的乙酰化对抗肥大和心力衰竭的作用仍然知之甚少。阐明
酮体作用的分子机制超越燃料,介导抗肥厚和促
在不引起有害影响的情况下产生能量效应,是建立酮体的最重要问题
作为 HF 的治疗选择。我们最近发现赖氨酸乙酰转移酶 6A (KAT6A) 在
低碳水化合物(LC)饮食介导的酮体增加对心脏有影响,这与
压力超负荷后出现肥厚和心力衰竭。因此,我们在这里询问 KAT6A 的乙酰化是否至关重要
参与酮体对抗心脏病的作用。我们的研究提供了乙酰化的证据
KAT6A 抑制去氧肾上腺素诱导的肥大并改善心肌细胞的能量稳态
体外。然而,KAT6A 乙酰化如何调节心脏形态和功能仍不清楚。基于
基于这些令人兴奋的观察结果,我们提出了 KAT6A 乙酰化在病理性肥大中的新作用,
向高频的过渡。以及我们使用蛋白质组学和基因组学进行的研究的令人惊讶的发现
通过分析,我们假设酮体促进 KAT6A 的乙酰化,从而刺激 AMPK
心脏中的信号传导抑制蛋白质合成并维持能量稳态,从而抑制
病理性肥大并转变为心力衰竭。为了解决这个假设,我们将进行以下操作
实验。在目标 1 中,我们将确定 KAT6A 乙酰化在压力过载诱导的中的重要性
通过使用新生成的 KAT6A 乙酰化抗性敲入小鼠和 AAV- 体内肥大和心力衰竭
KAT6A 乙酰化模拟突变体。在目标 2 中,我们将展示 AMPK 在 KAT6A 中的关键参与
通过药理学和基因抑制 AMPK 发挥作用。我们将进一步阐明其机制
AMPK 通过分子信号传导和生物测定被 KAT6A 激活。本次活动的长远目标
该项目旨在确定特异性调节酮体-KAT6A-AMPK通路的治疗靶点
与心脏肥大和心力衰竭的一级和二级预防策略相关。
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 }}
Michinari Nakamura其他文献
Michinari Nakamura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('Michinari Nakamura', 18)}}的其他基金
Lysine Acetyltransferase 6A in Health and Cardiac Diseases
赖氨酸乙酰转移酶 6A 在健康和心脏病中的作用
- 批准号:
10097160 - 财政年份:2021
- 资助金额:
$ 39.25万 - 项目类别:
Lysine Acetyltransferase 6A in Health and Cardiac Diseases
赖氨酸乙酰转移酶 6A 在健康和心脏病中的作用
- 批准号:
10652604 - 财政年份:2021
- 资助金额:
$ 39.25万 - 项目类别:
相似海外基金
Dissecting out differential molecular phenotypes across Lysine(K) AcetylTransferase mutations in mouse development
剖析小鼠发育过程中赖氨酸(K)乙酰转移酶突变的差异分子表型
- 批准号:
10727966 - 财政年份:2023
- 资助金额:
$ 39.25万 - 项目类别:
Targeting lysine acetyltransferase MOF/KAT8 in lung cancer
靶向赖氨酸乙酰转移酶 MOF/KAT8 在肺癌中的作用
- 批准号:
10601761 - 财政年份:2023
- 资助金额:
$ 39.25万 - 项目类别:
Defining the cell-type specific role of histone acetyltransferase KAT2a in nucleus accumbens D1 medium spiny neurons as a driver of cocaine use disorder
定义组蛋白乙酰转移酶 KAT2a 在伏隔核 D1 中型多棘神经元中作为可卡因使用障碍驱动因素的细胞类型特异性作用
- 批准号:
10679238 - 财政年份:2023
- 资助金额:
$ 39.25万 - 项目类别:
Roles of lysine acetyltransferase 6 complexes in cerebral development and neurodevelopmental disorders
赖氨酸乙酰转移酶 6 复合物在大脑发育和神经发育障碍中的作用
- 批准号:
479754 - 财政年份:2023
- 资助金额:
$ 39.25万 - 项目类别:
Operating Grants
Development of p300/CBP histone acetyltransferase inhibitors for oncogene-driven cancers
开发用于癌基因驱动癌症的 p300/CBP 组蛋白乙酰转移酶抑制剂
- 批准号:
10344246 - 财政年份:2022
- 资助金额:
$ 39.25万 - 项目类别:
Examination of the Histone Acetyltransferase CBP in the Remodelling of Thermogenic Adipose Tissues
组蛋白乙酰转移酶 CBP 在生热脂肪组织重塑中的检测
- 批准号:
486467 - 财政年份:2022
- 资助金额:
$ 39.25万 - 项目类别:
Studentship Programs
Nuclear activity of carnitine acetyltransferase
肉毒碱乙酰转移酶的核活性
- 批准号:
RGPIN-2018-06089 - 财政年份:2022
- 资助金额:
$ 39.25万 - 项目类别:
Discovery Grants Program - Individual
Development of p300/CBP histone acetyltransferase inhibitors for oncogene-driven cancers
开发用于癌基因驱动癌症的 p300/CBP 组蛋白乙酰转移酶抑制剂
- 批准号:
10627744 - 财政年份:2022
- 资助金额:
$ 39.25万 - 项目类别:
Characterizing the role of the NuA3 histone acetyltransferase complex during transcription
表征 NuA3 组蛋白乙酰转移酶复合物在转录过程中的作用
- 批准号:
557615-2021 - 财政年份:2022
- 资助金额:
$ 39.25万 - 项目类别:
Postdoctoral Fellowships
Structural and functional studies of histone acetyltransferase complexes
组蛋白乙酰转移酶复合物的结构和功能研究
- 批准号:
RGPIN-2018-03951 - 财政年份:2022
- 资助金额:
$ 39.25万 - 项目类别:
Discovery Grants Program - Individual