AGE/RAGE Interaction in Patients with Pressure Overload-Induced Heart Failure
压力过载诱发心力衰竭患者中 AGE/RAGE 的相互作用
基本信息
- 批准号:8257862
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-04-01 至 2015-03-31
- 项目状态:已结题
- 来源:
- 关键词:Advanced Glycosylation End ProductsAftercareAnimal ModelAortic Valve StenosisBindingBiopsyChloride IonChloridesChronicClinicalClinical ResearchCollagenCollagen ReceptorsComplementary DNACoronary Artery BypassDevelopmentDiastolic heart failureEFRACFibroblastsGoalsGrant ReviewHealthcareHeart failureHypertensionInfectionLeftLeft Ventricular HypertrophyLigand BindingLigandsMeasuresMicroRNAsMolecularMorbidity - disease rateMyocardialMyocardial tissueMyocardiumPathway interactionsPatientsPerformancePhenotypePlayPopulationProgram ReviewsPropertyProteinsRegulationRisk FactorsRoleSignal TransductionSigns and SymptomsStructureTestingTissuesTranslationsVentricularVeteransViralbasecare burdencrosslinkdisabilityeffective therapyevidence based guidelinesgain of functionloss of functionmRNA Transcript Degradationmortalitynovelpressurepreventpublic health relevancereceptorreceptor for advanced glycation endproductsresearch studyresponse
项目摘要
DESCRIPTION (provided by applicant):
In response to the chronic pressure-overload caused by arterial hypertension or aortic valve stenosis, the myocardium undergoes hypertrophic remodeling that results in the development of left ventricular hypertrophy (LVH). These structural changes are associated with mild - moderate alterations in diastolic performance and increased left ventricular diastolic chamber stiffness. However, these initial compensatory changes in structure and function do not result in the development of clinical heart failure; these patients have compensatory LVH. Eventually, some patients decompensate and develop clinical heart failure. In these patients, hypertrophic remodeling is associated with severe alterations in diastolic performance and severely increased myocardial stiffness; these patients have diastolic heart failure (DHF). The mechanisms that contribute to the transition from compensated LVH to decompensated DHF in patients with chronic pressure-overload are not clearly defined. DHF is a major cause of morbidity and mortality in the Veteran population. Despite this health care burden, there are no evidence based recommendations for treatment that will reduce the mortality, morbidity or disability suffered by Veterans with DHF. In large part, these deficiencies may result from the lack of clear understanding of what basic, fundamental, underlying cellular and molecular mechanisms cause DHF. The fundamental goal of my VA Merit Review program is to identify the mechanisms that cause diastolic heart failure. Based on the preliminary clinical studies in patients with aortic valve stenosis (AS) presented in this application and studies in animal models of pressure-overload performed during my previous Merit Review grants, we hypothesized that the formation of advanced glycation end products (AGEs) and their interaction with the receptor for AGEs (RAGE) are a primary determinants of myocardial stiffness, collagen structure and fibroblast phenotype. Furthermore, we hypothesized that three AGE-dependent mechanisms contribute to the transition from compensated LVH to decompensated diastolic heart failure in patients with AS. First, chronic PO causes the formation of AGEs that increase AGE-induced collagen cross-links, modify the material properties of collagen and increase myocardial stiffness. Second, chronic AGE-ligand stimulation of the RAGE receptor results in a change in fibroblast phenotype characterized by increased RAGE and collagen synthesis. Third, the change in fibroblast phenotype is dependent upon regulation of microRNAs (miRs) that effect mRNA degradation or protein translation, specifically miRs that target AGE/RAGE dependent pathways and effect RAGE and collagen synthesis. We will test these hypotheses using three Specific Aims. Specific Aim 1: Demonstrate that increased AGE- induced collagen cross-links contribute to increases in stiffness in AS patients with compensated LVH and a change in fibroblast phenotype contributes to the transition in AS patients to decompensated DHF. Specific Aim 2: Demonstrate that an increase in AGE/RAGE interaction contributes to a change fibroblast phenotype characterized by an increase in RAGE and collagen synthesis. Specific Aim 3: Demonstrate that specific endogenous microRNAs that target RAGE prevent or enhance a change in fibroblast phenotype. This completely revised proposal will more directly examine three specific AGE-dependent mechanisms that contribute to the development of compensated left ventricular hypertrophy and the transition to diastolic heart failure.
PUBLIC HEALTH RELEVANCE:
The most common cause of CV morbidity and mortality in the Veteran population is chronic heart failure (HF). LV pressure-overload (hypertension and aortic valve stenosis) is the largest risk factor for the development of HF. Over 50% of HF patients develop symptoms and signs of clinical HF despite a normal (or preserved) ejection fraction. These patients are said to have diastolic heart failure (DHF). Patients with DHF have an enormous increase in mortality, morbidity, and disability. Despite this unmet health care burden, there is no effective treatment for these Veterans with DHF. This lack of effective treatment is caused by the fact that we do not have a clear understanding of what basic, fundamental, underlying cellular and molecular mechanisms cause DHF. My goal is to identify the mechanisms that cause pressure-overload induced DHF and then to use these mechanisms as a target to develop novel, effective treatment for VA patients with heart failure.
描述(由申请人提供):
为了应对由动脉高血压或主动脉瓣狭窄引起的慢性压力释放,心肌经历肥厚的重塑,导致左心室肥大(LVH)的发展。这些结构变化与舒张性性能的温和变化有关,左心室舒张期僵硬增加。但是,这些结构和功能的最初补偿性变化并不能导致临床心力衰竭的发展。这些患者具有补偿性LVH。最终,一些患者使临床心力衰竭失去并发挥临床心力衰竭。在这些患者中,肥厚的重塑与舒张性性能的严重改变有关,并严重增加心肌僵硬。这些患者患有舒张期心力衰竭(DHF)。尚未明确定义导致从补偿LVH到代偿性DHF过渡到代偿DHF的过渡的机制。 DHF是退伍军人人口发病率和死亡率的主要原因。尽管有这种医疗保健负担,但没有基于证据的治疗建议可以减少DHF退伍军人遭受的死亡率,发病率或残疾。在很大程度上,这些缺陷可能是由于缺乏对基本,基本,潜在的细胞和分子机制导致DHF的明确了解。我的VA功绩审查计划的基本目标是确定引起舒张期心力衰竭的机制。 根据该应用中主动脉瓣狭窄(AS)的初步临床研究,以及在我先前的优异审查拨款期间进行的压力超负荷的动物模型中的研究,我们假设形成了高级糖基化终产物(AGES)的形成及其与Ages受体的相互作用(rage)是肌强化的主要测定剂,是肌的结构。此外,我们假设三种依赖年龄的机制有助于从AS患者中从补偿LVH到代偿性舒张性心力衰竭的过渡。首先,慢性PO会导致年龄的形成,从而增加了年龄引起的胶原蛋白交联,改变胶原蛋白的材料特性并增加心肌僵硬。其次,对愤怒受体的慢性年龄刺激导致成纤维细胞表型的变化,其特征是愤怒和胶原蛋白合成增加。第三,成纤维细胞表型的变化取决于影响mRNA降解或蛋白质翻译的microRNA(miR),特别是针对年龄/愤怒依赖性途径的miR和效应rage and Rage and Collagen合成。我们将使用三个特定目标检验这些假设。具体目标1:证明年龄诱导的胶原交联的增加会导致AS AS AS AS AS AS AS AS AS AS REDSED LVH患者的刚度增加,而成纤维细胞表型的变化会导致AS患者的过渡到代偿DHF的转变。具体目标2:证明年龄/愤怒相互作用的增加有助于变化成纤维细胞表型,其特征是愤怒和胶原蛋白合成的增加。特定目的3:证明靶向愤怒的特定内源性microRNA可防止或增强成纤维细胞表型的变化。这项完全修订的建议将更直接地检查三种特定年龄依赖的机制,这些机制有助于弥补左心室肥大的发展以及向舒张性心力衰竭的过渡。
公共卫生相关性:
在退伍军人人口中,CV发病率和死亡率的最常见原因是慢性心力衰竭(HF)。 LV压力超载(高血压和主动脉瓣狭窄)是HF发展的最大危险因素。尽管有正常(或保留)的射血分数,但超过50%的HF患者仍会出现症状和临床HF的迹象。据说这些患者患有舒张期心力衰竭(DHF)。 DHF患者的死亡率,发病率和残疾人数巨大。尽管有这种未满足的医疗保健负担,但对于这些退伍军人来说,尚无有效的DHF治疗方法。缺乏有效的治疗是由于我们对基本,基本的,基本的细胞和分子机制的理解没有清楚的理解。我的目标是确定导致压力越过诱发的DHF的机制,然后将这些机制用作为心力衰竭的VA患者开发新颖,有效治疗的目标。
项目成果
期刊论文数量(0)
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Michael R Zile其他文献
1058-69 Modeling and prediction of acute hemodynamic effects of an arterial assist device
- DOI:
10.1016/s0735-1097(04)91705-6 - 发表时间:
2004-03-03 - 期刊:
- 影响因子:
- 作者:
Salvatore A Chiaramida;Naveen L Pereira;Michael R Zile;Christopher D Nielsen;Adrian B VanBakel;Donna M Meyer;Ying Sun - 通讯作者:
Ying Sun
Michael R Zile的其他文献
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{{ truncateString('Michael R Zile', 18)}}的其他基金
Extracellular Matrix in Hypertensive Heart Disease & Transition to Heart Failure
高血压心脏病中的细胞外基质
- 批准号:
9477758 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Extracellular Matrix in Hypertensive Heart Disease & Transition to Heart Failure
高血压心脏病中的细胞外基质
- 批准号:
9100853 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Extracellular Matrix in Hypertensive Heart Disease & Transition to Heart Failure
高血压心脏病中的细胞外基质
- 批准号:
9273602 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Extracellular Matrix in Hypertensive Heart Disease & Transition to Heart Failure
高血压心脏病中的细胞外基质
- 批准号:
8903566 - 财政年份:2014
- 资助金额:
-- - 项目类别:
AGE/RAGE Interaction in Patients with Pressure Overload-Induced Heart Failure
压力过载诱发心力衰竭患者中 AGE/RAGE 的相互作用
- 批准号:
8698368 - 财政年份:2011
- 资助金额:
-- - 项目类别:
AGE/RAGE Interaction in Patients with Pressure Overload-Induced Heart Failure
压力过载诱发心力衰竭患者中 AGE/RAGE 的相互作用
- 批准号:
8140701 - 财政年份:2011
- 资助金额:
-- - 项目类别:
AGE/RAGE Interaction in Patients with Pressure Overload-Induced Heart Failure
压力过载诱发心力衰竭患者中 AGE/RAGE 的相互作用
- 批准号:
8392975 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Connexin Distribution in Physiological Versus Pathological Cardiac Hypertrophy
生理性与病理性心脏肥大中的连接蛋白分布
- 批准号:
8391535 - 财政年份:2009
- 资助金额:
-- - 项目类别:
DIASTOLIC HEART FAILURE: DEFINING CARDIOCYTE MECHANISMS
舒张性心力衰竭:定义心肌细胞机制
- 批准号:
6808271 - 财政年份:2003
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-- - 项目类别:
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