Regulation of Myocardial Phospholipases and Lipases in Diabetic Myocardium
糖尿病心肌中心肌磷脂酶和脂肪酶的调节
基本信息
- 批准号:10551194
- 负责人:
- 金额:$ 77.98万
- 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:2013-06-01 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:12-HETEAblationAccelerationAcuteAcyl Coenzyme AAcyltransferaseAnkyrin RepeatArrhythmiaBindingBioinformaticsC-terminalCalmodulinCalpainCardiac MyocytesCatalytic DomainCause of DeathComplexDeveloped CountriesDevelopmentDiabetes MellitusDissectionEicosanoid ModulationEicosanoidsEngineeringEsterificationGenerationsGeneticGenetic EngineeringGenetic TranscriptionGlycerolGrantHeartHeart DiseasesHigh Fat DietHoloenzymesHydrolysisHydroxyeicosatetraenoic AcidsIL8 geneIn VitroIndustrializationInfarctionInflammationInflammation MediatorsInflammatoryInsulin-Dependent Diabetes MellitusIschemiaKnock-outKnockout MiceLigandsLipaseLipidsLysophospholipaseLysophospholipidsMacrophageMass Spectrum AnalysisMediatingMetabolicMetabolic PathwayMetabolismModelingMolecularMusMyocardialMyocardial InfarctionMyocardial IschemiaMyocardiumNon-Insulin-Dependent Diabetes MellitusPathologicPathway interactionsPatternPenetrationPerformancePhospholipasePhospholipidsPhosphorylationPhysiologic pulsePlasmalogensPlayPost-Translational Protein ProcessingProductionProtein IsoformsProteolysisProteolytic ProcessingRegional PerfusionRegulationResearchResolutionRisk FactorsRoleSignal PathwaySignal TransductionSignaling MoleculeSiteSocietiesSpecificityStable Isotope LabelingSterilityStructureTissuesTransacylaseTransgenic MiceType 2 diabeticVertebral columnWild Type MouseX-Ray Crystallographyacylcarnitinecalmodulin-dependent protein kinase IIcomorbiditydiabeticdiabetic cardiomyopathydiabetic patientexperimental studyhemodynamicsin vivoinsightinterestmetabolic ratemitochondrial dysfunctionmonocytemouse toll-like receptor 4nanomolarpreferencepreventreceptorstable isotopetransacylationtype I and type II diabetes
项目摘要
ABSTRACT
Heart disease is the most common cause of death in industrialized nations. The presence of underlying diabetes
is the greatest risk factor for the progression of heart disease. During the current grant interval, we have
discovered previously unknown lipid metabolic pathways and signaling molecules which lead to the generation
of eicosanoid-lysophospholipids. Remarkably, the vast majority of eicosanoids in myocardium were found to be
esterified to the glycerol backbone of lysophospholipids. In addition, induction of Type I diabetes in wild-type
mice or ischemic damage in isolated wild-type mouse hearts resulted in dramatic increases in pro-inflammatory
eicosanoid-lysophospholipids. This new class of phospholipids serve as inflammatory mediators by inducing the
release of TNFa from monocytes or macrophages. Importantly, genetic ablation of iPLA2g (PNPLA8)
substantially decreased the levels of eicosanoid-lysophospholipids in myocardium in the diabetic state, during
myocardial ischemia and synergistically decreased their synthesis in diabetic myocardium rendered ischemic.
Accordingly, we propose that iPLA2g plays a central role in the pathophysiologic development of diabetic heart
disease and promotes the lethal sequelae of diabetic cardiomyopathy. In Specific Aim 1, we will utilize stable
isotope labeling of isolated perfused mouse hearts from genetically engineered cardiac myocyte-specific
conditional iPLA2g knockout mice we have generated. These studies will investigate the roles of iPLA2g in the
metabolic flux of: 1) non-esterified and esterified eicosanoids; 2) eicosanoid-lysophospholipids; and 3) other
salient oxidized phospholipids. Stable isotope pulse-chase experiments followed by penetrating bioinformatic
analyses will determine rates of metabolic flux through these newly discovered pathways. Translationally, we
will explore the impact of Type 2 diabetes on myocardial ischemic damage and the potential salvage of ischemic
myocardium in cardiac myocyte-specific iPLA2g KO mice we engineered. Endpoints of analysis include infarct
size, hemodynamic performance, and post-translational modifications of iPLA2g. In Specific Aim 2, we will utilize
cardiac myocyte-specific iPLA2b KO mice we have generated to explore the role of iPLA2b in promoting
myocardial ischemic damage and arrhythmias in WT vs. iPLA2b KO mice in the context of Type II diabetes. Next,
we will determine the ability of iPLA2b to catalyze acyltransferase or transacylase mediated re-esterification of
eicosanoid-lysophospholipids to generate oxidized phospholipids which have been implicated in damage
associated molecular patterns. In Specific Aim 3, the mechanisms through which a high fat diet induces
eicosanoid-lysolipid synthesis accompanied by inflammation and mitochondrial dysfunction will be studied. The
roles of lysophospholipases in modulating eicosanoid-lysophospholipid levels and activation mechanisms for
iPLA2g will be examined. Collectively, the proposed studies will establish the significance of iPLA2g and iPLA2b
in mediating the newly identified pathways of eicosanoid-lysophospholipid synthesis and metabolism and
determine their impact on diabetic cardiomyopathy and acute ischemic damage in diabetic hearts.
摘要
心脏病是工业化国家最常见的死亡原因。潜在糖尿病的存在
是心脏病进展的最大风险因素。在目前的授予间隔期间,我们有
发现了以前未知的脂代谢途径和信号分子,导致了
二十烷类溶血磷脂。值得注意的是,心肌中的绝大多数二十烷类化合物被发现是
酯化为溶血磷脂的甘油骨架。此外,野生型I型糖尿病的诱因
小鼠或野生型小鼠离体心的缺血损伤导致促炎因子显著增加
二十烷类溶血磷脂。这类新的磷脂作为炎症介质通过诱导
单核细胞或巨噬细胞释放肿瘤坏死因子α。重要的是,iPLA2g(PNPLA8)的遗传消融
显著降低糖尿病状态下心肌中二十烷类溶血磷脂的水平
心肌缺血并协同减少糖尿病心肌缺血时它们的合成。
因此,我们认为iPLA2g在糖尿病心脏的病理生理发展中起核心作用。
并促进糖尿病心肌病的致命后遗症。在具体目标1中,我们将使用稳定
基因工程心肌细胞特异性离体灌流小鼠心脏的同位素标记
我们已经产生了条件iPLA2g基因敲除小鼠。这些研究将探讨iPLA2g在细胞周期中的作用。
代谢通量:1)非酯化和酯化二十烷类化合物;2)二十烷类溶血磷脂;以及3)其他
显著的氧化磷脂。稳定同位素脉冲追逐实验及穿透生物信息学
分析将确定通过这些新发现的途径的代谢流量的速率。从翻译上讲,我们
将探讨2型糖尿病对心肌缺血损伤的影响及对缺血的潜在挽救作用
我们设计的心肌细胞特异性iPLA2g KO小鼠的心肌。分析的终点包括脑梗塞
IPLA2g的大小、血流动力学性能和翻译后修饰。在具体目标2中,我们将利用
我们建立了心肌细胞特异性的iPLA2b KO小鼠,以探索iPLA2b在促进
WT与iPLA2b KO小鼠在II型糖尿病背景下的心肌缺血性损伤和心律失常。下一首,
我们将确定iPLA2b催化酰基转移酶或转酰基酶介导的再酯化的能力
二十烷类溶血磷脂生成氧化磷脂,已被认为与损害有关
相关的分子模式。在具体目标3中,高脂肪饮食诱导的机制
将研究伴随炎症和线粒体功能障碍的二十烷类溶脂合成。这个
溶血磷脂酶在调节二十烷基类溶血磷脂水平中的作用及其激活机制
将对iPLA2g进行检查。总的来说,拟议的研究将确立iPLA2g和iPLA2b的意义
在介导新发现的二十烷基类溶血磷脂合成和代谢途径以及
确定它们对糖尿病心肌病和糖尿病心脏急性缺血性损害的影响。
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)
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RICHARD W GROSS其他文献
RICHARD W GROSS的其他文献
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{{ truncateString('RICHARD W GROSS', 18)}}的其他基金
Novel Lipid 2nd Messengers Regulating Bioenergetics and Signaling in Human Myocardium
调节人体心肌生物能和信号传导的新型脂质第二信使
- 批准号:
10593961 - 财政年份:2016
- 资助金额:
$ 77.98万 - 项目类别:
Novel Lipid 2nd Messengers Regulating Bioenergetics and Signaling in Human Myocardium
调节人体心肌生物能和信号传导的新型脂质第二信使
- 批准号:
10378709 - 财政年份:2016
- 资助金额:
$ 77.98万 - 项目类别:
NOVEL LIPID 2ND MESSENGERS REGULATING BIOENERGETICS AND SIGNALING IN HUMAN MYOCARDIUM
调节人体心肌生物能量和信号传导的新型脂质第二信使
- 批准号:
9281066 - 财政年份:2016
- 资助金额:
$ 77.98万 - 项目类别:
Novel Lipid 2nd Messengers Regulating Bioenergetics and Signaling in Human Myocardium
调节人体心肌生物能和信号传导的新型脂质第二信使
- 批准号:
10211266 - 财政年份:2016
- 资助金额:
$ 77.98万 - 项目类别:
THE INTEGRATED ROLES OF IPLA2G IN OBESITY, INFLAMMATION AND HEPATIC DYSFUNCTION
IPLA2G 在肥胖、炎症和肝功能障碍中的综合作用
- 批准号:
8817361 - 财政年份:2014
- 资助金额:
$ 77.98万 - 项目类别:
THE INTEGRATED ROLES OF IPLA2G IN OBESITY, INFLAMMATION AND HEPATIC DYSFUNCTION
IPLA2G 在肥胖、炎症和肝功能障碍中的综合作用
- 批准号:
9325506 - 财政年份:2014
- 资助金额:
$ 77.98万 - 项目类别:
REGULATION OF MYOCARDIAL PHOSPHOLIPASES AND LIPASES IN DIABETIC MYOCARDIUM
糖尿病心肌中心肌磷脂酶和脂肪酶的调节
- 批准号:
8483030 - 财政年份:2013
- 资助金额:
$ 77.98万 - 项目类别:
REGULATION OF MYOCARDIAL PHOSPHOLIPASES AND LIPASES IN DIABETIC MYOCARDIUM
糖尿病心肌中心肌磷脂酶和脂肪酶的调节
- 批准号:
9309220 - 财政年份:2013
- 资助金额:
$ 77.98万 - 项目类别:
REGULATION OF MYOCARDIAL PHOSPHOLIPASES AND LIPASES IN DIABETIC MYOCARDIUM
糖尿病心肌中心肌磷脂酶和脂肪酶的调节
- 批准号:
9065644 - 财政年份:2013
- 资助金额:
$ 77.98万 - 项目类别:
Regulation of Myocardial Phospholipases and Lipases in Diabetic Myocardium
糖尿病心肌中心肌磷脂酶和脂肪酶的调节
- 批准号:
10367196 - 财政年份:2013
- 资助金额:
$ 77.98万 - 项目类别:
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