Mechanism of metabolic remodeling in the diabetic heart
糖尿病心脏代谢重塑机制
基本信息
- 批准号:10705337
- 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:2022-09-22 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:3-hydroxy-3-methylglutaryl-coenzyme AAcetyl Coenzyme AAcetylationAttenuatedBindingBiopsyCardiacCardiac MyocytesCarnitineCarrier ProteinsCitrate (si)-SynthaseCitric Acid CycleCoenzyme ACoenzyme A-TransferasesConsumptionCrossbreedingDeacetylaseDeacetylationDiabetes MellitusEnzymesFatty AcidsGenetic TranscriptionGlucoseHeartHeart TransplantationHeart failureHomeoboxHyperglycemiaInvestigationKetone BodiesKnowledgeLipidsMeasuresMetabolicMetabolismMitochondriaMitochondrial ProteinsMolecularMolecular TargetMusMyocardial dysfunctionPathogenesisPatientsPromoter RegionsProteinsRegulationRiskRoleSirtuinsSyndromeTestingTransferaseTransgenic MiceUntranslated RegionsZinc Fingersbeta-adrenergic receptorcardiometabolismdiabeticdiabetic ratfatty acid metabolismfatty acid oxidationfollow-upimprovedinsightketogenesismitochondrial dysfunctionnew therapeutic targetnon-diabeticnoveloverexpressionoxidationpreventreceptor functionresponsesuccinyl-coenzyme Auptake
项目摘要
PROJECT SUMMARY
To compensate for the decreased glucose oxidation, diabetic cardiomyocytes increase lipid uptake. Due to
mitochondrial dysfunction, cardiomyocytes could not efficiently utilize lipids leading to accumulation of fatty acetyl
CoA, a product of fatty acid oxidation. High levels of acetyl CoA promotes ketogenesis by inducing the rate-
limiting enzyme 3-Hydroxy-3-MethylGlutaryl-CoA-Synthase-2 (HMGCS2), which produces ketone bodies.
Ketogenesis inhibits consumption of ketone bodies via ketolysis where the rate-limiting enzyme is succinyl-CoA:
3-oxoacid CoA transferase (SCOT). Reduced ketolysis decreases energy in the diabetic heart. In our novel
diabetic Akita mice with cardiac-specific overexpression in the cardiomyocytes (Akita/miR-133aTg), intramyocyte
lipid accumulation is prevented. Our investigation revealed that miR-133a targets 3/UTR of Zinc finger E-box-
bonding homeobox (ZEB). ZEB inhibits mitochondrial deacetylase sirtuin-3 (SIRT3). SIRT3 improves
mitochondrial function by activating mitochondrial proteins via deacetylation. Increased mitochondrial function
decreases the fatty acetyl CoA accumulation, which is required for both ketogenesis and lipid accumulation.
Hypothesis: Overexpression of miR-133a in the DM heart will promote fatty acid metabolism to decrease lipid
accumulation and ketogenesis, which overall stimulates ketolysis resulting in improved energy efficiency.
Aim 1: Test the hypothesis that increased cardiac miR-133a improves fatty acid metabolism to reduce
lipid accumulation in the diabetic heart by targeting ZEB. Evaluate the effect of miR-133a on diabetes-
induced FA uptake and metabolism, ZEB, and lipid accumulation in the diabetic heart.
Aim 2: Test the hypothesis that increased fatty acetyl CoA in mitochondria induces ketogenesis in the
diabetic heart by upregulating HMGCS2. Evaluate the effect of SIRT3 on fatty acetyl CoA, HMGCS2, and
ketogenesis in the diabetic heart.
Aim 3: Test the hypothesis that cardiac ketogenesis prevents ketolysis to reduce energy in the diabetic
heart by suppressing SCOT. Evaluate ketolysis and cardiac energy in the HMGCS2-inhibited diabetic heart.
Impact: The completion of these aims will: 1) enhance our knowledge on metabolic remodeling in the DM
heart, 2) provide new molecular targets to modulate metabolic flux in the DM heart, 3) provide insight to
improve cardiac energy efficiency in the diabetic heart, and 4) render metabolic targets that can be tested in
non-diabetic heart failure where metabolism is deranged.
项目总结
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Deciphering MMP9's dual role in regulating SOD3 through protein-protein interactions.
解读 MMP9 通过蛋白质-蛋白质相互作用调节 SOD3 的双重作用。
- DOI:10.1139/cjpp-2023-0256
- 发表时间:2024
- 期刊:
- 影响因子:2.1
- 作者:Gawargi,FlobaterI;Mishra,ParasK
- 通讯作者:Mishra,ParasK
{{
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 }}
Paras Kumar Mishra其他文献
Paras Kumar Mishra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('Paras Kumar Mishra', 18)}}的其他基金
Exercise and H2S mitigate homocysteine-mediated beta2-adrenergic receptor dysfunc
运动和 H2S 减轻同型半胱氨酸介导的 β2 肾上腺素能受体功能障碍
- 批准号:
8505850 - 财政年份:2013
- 资助金额:
$ 40.04万 - 项目类别:
Inflammation, miRNA and autophagy in diabetes
糖尿病中的炎症、miRNA 和自噬
- 批准号:
8603282 - 财政年份:2013
- 资助金额:
$ 40.04万 - 项目类别:
Inflammation, miRNA and autophagy in diabetes
糖尿病中的炎症、miRNA 和自噬
- 批准号:
8711702 - 财政年份:2013
- 资助金额:
$ 40.04万 - 项目类别:
Exercise and H2S mitigate homocysteine-mediated beta2-adrenergic receptor dysfunc
运动和 H2S 减轻同型半胱氨酸介导的 β2 肾上腺素能受体功能障碍
- 批准号:
8729004 - 财政年份:2013
- 资助金额:
$ 40.04万 - 项目类别:
Inflammation, miRNA and autophagy in diabetes
糖尿病中的炎症、miRNA 和自噬
- 批准号:
8883686 - 财政年份:2013
- 资助金额:
$ 40.04万 - 项目类别:
Exercise and H2S mitigate homocysteine-mediated beta2-adrenergic receptor dysfunc
运动和 H2S 减轻同型半胱氨酸介导的 β2 肾上腺素能受体功能障碍
- 批准号:
8870418 - 财政年份:2013
- 资助金额:
$ 40.04万 - 项目类别:
Inflammation, miRNA and autophagy in diabetes
糖尿病中的炎症、miRNA 和自噬
- 批准号:
9313923 - 财政年份:2013
- 资助金额:
$ 40.04万 - 项目类别:
Inflammation, miRNA and autophagy in diabetes
糖尿病中的炎症、miRNA 和自噬
- 批准号:
9109667 - 财政年份:2013
- 资助金额:
$ 40.04万 - 项目类别:
相似海外基金
The molecular basis for how acetyl-coenzyme A links metabolism to gene expression
乙酰辅酶 A 如何将代谢与基因表达联系起来的分子基础
- 批准号:
8783415 - 财政年份:2014
- 资助金额:
$ 40.04万 - 项目类别:
The molecular basis for how acetyl-coenzyme A links metabolism to gene expression
乙酰辅酶 A 如何将代谢与基因表达联系起来的分子基础
- 批准号:
8996048 - 财政年份:2014
- 资助金额:
$ 40.04万 - 项目类别:
The molecular basis for how acetyl-coenzyme A links metabolism to gene expression
乙酰辅酶 A 如何将代谢与基因表达联系起来的分子基础
- 批准号:
9125794 - 财政年份:2014
- 资助金额:
$ 40.04万 - 项目类别: