Mechanisms of Cardiac Remodeling in Offspring of Diabetic Mothers
糖尿病母亲后代心脏重构的机制
基本信息
- 批准号:7290430
- 负责人:
- 金额:$ 28.64万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-09-25 至 2010-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAnimalsApoptosisApoptoticBirthCardiacCardiac MyocytesCardiomyopathiesCardiovascular systemCell CountCell VolumesCellsConfocal MicroscopyCoronaryDiabetic motherEchocardiographyEpidemicFlow CytometryFunctional disorderGestational DiabetesGoalsHeartHeart HypertrophyHyperplasiaHypertrophic CardiomyopathyHypertrophyImmunoblottingInjuryInterventionIschemiaLeft ventricular structureLifeLigationMAPK14 geneMeasurementMeasuresMitogen-Activated Protein Kinase InhibitorMitogen-Activated Protein KinasesModelingMuscle CellsNeonatalNewborn InfantNumbersObesityPathway interactionsPhosphotransferasesPhysiological reperfusionPopulationPredispositionPublic HealthRattusRegulationRelative (related person)Reperfusion TherapyResearch PersonnelResolutionSignal PathwayTestingTimeVentricularVentricular RemodelingVentricular septumcell typecongenital heart disorderdiabeticheart dimension/sizeimprovedin vivoinfant of diabetic motherinhibitor/antagonistpostnatalprogramspupsizeventricular hypertrophy
项目摘要
DESCRIPTION (provided by applicant): Infants of diabetic mothers (IDM) are often born with hypertrophic cardiomyopathy. Regulation of remodeling of the newborn IDM heart and the long-term consequences of the neonatal cardiac hypertrophy are not well defined. The objectives of this proposal are to define the mechanisms that contribute to cardiac hypertrophy in the IDM, elucidate the signaling pathways that regulate postnatal normalization of cardiac mass, and identify the long-term sequelae. The specific aims that will be studied include: 1) Demonstrate that increased cardiac mass in the IDM heart is due to both hypertrophy and hyperplasia and that postnatal remodeling results in fewer, larger myocytes; 2) Verify that resolution of the IDM cardiomyopathy is due to activation of apoptosis regulated by the mitogen-activated protein (MAP) kinase signaling pathways; and 3) Demonstrate that adult hearts of IDM have greater susceptibility to an ischemia/reperfusion insult. We have developed a rat model of gestational diabetes that results in macrosomic rat pups with a hypertrophic cardiomyopathy. Using this model, morphometric studies of postnatal IDM hearts and isolated myocytes will be performed to address Aim 1. Aim 2 will be approached by administration of specific inhibitors of the MAP kinase signaling pathways to IDM and control rat pups. Activation of apoptosis will be assessed while remodeling of the heart will be evaluated by echocardiography and morphometric measurements. Both in vivo coronary ligation and isolated, perfused heart studies will be used to determine susceptibility to ischemic injury in the adult hearts of animals born to diabetic dams (Aim 3). The long-term objective of these studies is to understand the remodeling that takes place in the neonatal heart such that rationale strategies can be identified to enhance adaptive, and suppress maladaptive, changes in the hypertrophied IDM heart. The goal of these interventions will be to improve cardiac function later in life. The results from these studies should be applicable to other forms of congenital heart disease that are associated with ventricular hypertrophy and postnatal remodeling of the ventricles. Public Health Relevance: The obesity epidemic in the U.S. is accompanied by a greater number of diabetics and an increase in gestational diabetes. Significant hypertrophy of the newborn heart, which occurs in 30- 40% of infants of diabetic mothers, limits neonatal cardiac function and leads to long-term abnormalities of the cardiovascular system. Results from this proposal will define the mechanisms by which the IDM heart remodels after birth and develops long-term dysfunction, ultimately allowing interventions to be identified to protect both developing and mature hearts.
描述(由申请人提供):糖尿病母亲(IDM)的婴儿通常出生时患有肥厚性心肌病。新生儿 IDM 心脏重塑的调节以及新生儿心脏肥大的长期后果尚不清楚。该提案的目的是确定导致 IDM 心脏肥大的机制,阐明调节出生后心脏质量正常化的信号通路,并确定长期后遗症。将研究的具体目标包括: 1) 证明 IDM 心脏中心脏质量的增加是由于肥大和增生造成的,并且出生后重塑导致心肌细胞更少、更大; 2) 验证IDM心肌病的解决是由于丝裂原激活蛋白(MAP)激酶信号通路调节的细胞凋亡的激活所致; 3) 证明 IDM 成人心脏对缺血/再灌注损伤的敏感性更高。我们开发了一种妊娠糖尿病大鼠模型,该模型会导致巨大大鼠幼仔患有肥厚性心肌病。使用该模型,将对出生后 IDM 心脏和分离的肌细胞进行形态测量研究,以实现目标 1。通过对 IDM 和对照大鼠幼仔施用 MAP 激酶信号传导途径的特异性抑制剂来实现目标 2。将评估细胞凋亡的激活,同时将通过超声心动图和形态测量来评估心脏的重塑。体内冠状动脉结扎和离体灌注心脏研究将用于确定糖尿病母鼠所生动物成年心脏对缺血性损伤的敏感性(目标 3)。这些研究的长期目标是了解新生儿心脏中发生的重塑,以便确定合理的策略来增强肥大 IDM 心脏的适应性并抑制适应不良的变化。这些干预措施的目标是改善晚年的心脏功能。这些研究的结果应该适用于与心室肥大和产后心室重塑相关的其他形式的先天性心脏病。公共卫生相关性:美国的肥胖流行伴随着糖尿病患者数量的增加和妊娠期糖尿病的增加。糖尿病母亲所生婴儿中 30-40% 会出现新生儿心脏显着肥大,限制了新生儿心脏功能并导致心血管系统的长期异常。该提案的结果将定义 IDM 心脏在出生后重塑和发展长期功能障碍的机制,最终允许确定干预措施以保护发育中和成熟的心脏。
项目成果
期刊论文数量(0)
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THOMAS D SCHOLZ其他文献
THOMAS D SCHOLZ的其他文献
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{{ truncateString('THOMAS D SCHOLZ', 18)}}的其他基金
Mechanisms of Cardiac Remodeling in Offspring of Diabetic Mothers
糖尿病母亲后代心脏重构的机制
- 批准号:
7486766 - 财政年份:2006
- 资助金额:
$ 28.64万 - 项目类别:
Mechanisms Cardiac Remodeling Offspring Diabetic Mothers
糖尿病母亲后代的心脏重塑机制
- 批准号:
7233031 - 财政年份:2006
- 资助金额:
$ 28.64万 - 项目类别:
Mechanisms of Cardiac Remodeling in Offspring of Diabetic Mothers
糖尿病母亲后代心脏重构的机制
- 批准号:
7675391 - 财政年份:2006
- 资助金额:
$ 28.64万 - 项目类别:
Molecular and Cellular Research to Advance Child Health
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$ 28.64万 - 项目类别:
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- 资助金额:
$ 28.64万 - 项目类别:
THE NADH SHUTTLES AND METABOLIC ADAPTATION OF THE HEART
NADH 穿梭和心脏的代谢适应
- 批准号:
6536669 - 财政年份:2001
- 资助金额:
$ 28.64万 - 项目类别:
THE NADH SHUTTLES AND METABOLIC ADAPTATION OF THE HEART
NADH 穿梭和心脏的代谢适应
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$ 28.64万 - 项目类别:
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