Lipid Biomarkers for Diabetic Heart Disease

糖尿病心脏病的脂质生物标志物

• 批准号: 8286484
• 负责人: JEAN E. SCHAFFER
• 金额: $ 75.85万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-15 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8286484
• 关键词: Address; Adult; Animal Model; Animals; Biological Assay; Biological Markers; Biological Models; Blood; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular system; Cells; Ceramides; Clinical; Communities; Complement; Complication; Coronary Arteriosclerosis; Data; Diabetes Mellitus; Diagnosis; Disease; Disease Marker; Dyslipidemias; Early Diagnosis; Early treatment; Echocardiography; Ensure; Etiology; Fatty Acids; Fatty acid glycerol esters; Functional disorder; Future; Goals; Heart; Heart Diseases; Heart failure; Hemoglobin; Human; Immune; Incidence; Individual; Intervention; Investigation; Link; Lipids; Mass Spectrum Analysis; Measures; Metabolic; Methodology; Morbidity - disease rate; Myocardial; Myocardial Infarction; Myocardial dysfunction; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Pathogenesis; Patients; Phenotype; Plasma; Play; Population; Prevalence; Risk; Risk Factors; Rodent Model; Role; Sampling; Signal Pathway; Target Populations; Testing; Ventricular Remodeling; base; bench to bedside; cohort; diabetic; diabetic cardiomyopathy; disorder risk; glycemic control; heart function; human subject; improved; insight; lipid metabolism; metabolomics; modifiable risk; mortality; mouse model; multidisciplinary; novel; novel therapeutics; population based; prevent; success

DESCRIPTION (provided by applicant): Diabetes is associated with serious cardiovascular complications that include atherosclerotic coronary artery disease and myocardial dysfunction even in the absence of underlying coronary artery disease, a disorder termed diabetic cardiomyopathy (DCM). Data from studies of animal models and human subjects provide evidence that alterations in myocardial lipid metabolism is central to the pathogenesis of DCM, which early on can be asymptomatic, but which can progress to symptomatic heart failure. The ability to identify new disease markers to facilitate early detection and intervention is limited b inadequacies of existing measures of systemic and myocardial lipid metabolism in humans. In our Preliminary Studies, we have addressed this problem by using sensitive mass spectrometry-based metabolomics to identify two plasma very long-chain ceramides, Cer(22:0) and Cer(24:0), that are highly correlated with asymptomatic systolic dysfunction in obese and type 2 diabetic humans. Cell biological and mouse model studies suggest these species arise from the unique intersection of ectopic lipid accumulation and activation of innate immune signaling pathways. We hypothesize that plasma Cer(22:0) and Cer(24:0) reflect systemic alterations in lipid metabolism that can be exploited as novel biomarkers for DCM. While the diagnosis of cardiac dysfunction can be readily made noninvasively by echocardiogram, Cer(22:0) and Cer(24:0) track with pathophysiological consequences of ectopic lipid accumulation and thus have potential to predict individuals at risk, to further our understanding of disease mechanism, and to identify new treatment targets. We have assembled a multidisciplinary team to extend these findings by 1) Developing a robust high-throughput clinical assay for Cer(22:0) and Cer(24:0); 2) Validating and extending these findings in two existing cohorts of human subjects; 3) Exploring the mechanistic links between very long-chain ceramides and cardiac dysfunction in relevant mouse models of DCM; and 4) Defining the direction of causality in the relationships among lipid exposure, plasma ceramides, and cardiac function in humans with type 2 diabetes. Our approach has the potential to define an integrated measure of pathophysiologically relevant lipid exposure that can be used to track intervention success, data linking phenotype to a modifiable risk factor that is currently undertreated in the target population (dyslipidemia), and marker for future disease risk that can be acted upon to prevent clinically apparent morbidity and mortality. PUBLIC HEALTH RELEVANCE: Diabetes is associated with serious cardiovascular complications including heart failure that is unrelated to coronary artery disease. Scientific evidence suggests that blood fat levels play a major role in this complication. Our study will investigate the link between blood fat levels and heart function in adults with type 2 diabetes. Our goal is to develop new blood-based biomarkers of heart disease in diabetics and to provide insight into mechanisms underlying this disorder that will inform new therapeutic strategies.

描述（由申请人提供）：糖尿病与严重的心血管并发症有关，包括动脉粥样硬化冠状动脉疾病和心肌功能障碍，即使没有潜在的冠状动脉疾病，这种疾病称为糖尿病心肌病（DCM）。来自动物模型和人类受试者的研究的数据提供了证据，表明心肌脂质代谢的改变对于DCM发病机理至关重要，DCM的发病机理可能是无症状的，但可以发展为有症状的心力衰竭。鉴定新疾病标志物促进早期检测和干预的能力限制了人类现有系统性和心肌脂质代谢的现有量度不足。在我们的初步研究中，我们通过使用敏感的质谱代谢组学来解决这个问题，以识别两个血浆非常长链神经酰胺，CER（22：0）和CER（24：0），这些等离子体与无症状的肥胖症和2型和2型糖尿病人的无症状合理功能障碍高度相关。细胞生物学和小鼠模型研究表明，这些物种来自异位脂质积累和先天免疫信号通路的激活的独特相交。我们假设血浆CER（22：0）和CER（24：0）反映了脂质代谢的系统性改变，这些代谢可以被用作DCM的新生物标志物。虽然超声心动图（22：0）和CER（24：0）的心脏功能障碍的诊断很容易无创地进行，并且具有异位脂质积累的病理生理后果，因此具有预测风险的个体的潜力，以进一步预测我们对疾病机制的理解，并确定新的治疗范围。我们已经组建了一个多学科团队，以1）为CER（22：0）和CER（24：0）开发强大的高通量临床测定法。 2）验证并将这些发现扩展到两个现有的人类群体中； 3）探索DCM相关小鼠模型中非常长链神经酰胺与心脏功能障碍之间的机械联系； 4）在患有2型糖尿病的人类中，定义脂质暴露，血浆神经酰胺和心脏功能之间因果关系的方向。我们的方法有可能定义与病理生理相关的脂质暴露的综合度量，可用于跟踪干预成功，数据将表型连接到目前未在目标人群中尚未治疗的可修改风险因素（血脂血症）（柔韧性血症）以及可以预防临床明显的临床疾病和抵押率产生的疾病风险的标志。 公共卫生相关性：糖尿病与严重的心血管并发症有关，包括与冠状动脉疾病无关的心力衰竭。科学证据表明，血脂水平在这种并发症中起主要作用。我们的研究将研究2型糖尿病成人血脂水平与心脏功能之间的联系。我们的目标是开发糖尿病患者心脏病的新基于血液的生物标志物，并洞悉该疾病的基础机制，该疾病将为新的治疗策略提供信息。