Project 2 - Molecular and Cellular Mechanisms of Cardiometabolic Toxicity of VOCs

项目2——VOCs心脏代谢毒性的分子和细胞机制

• 批准号: 10693804
• 负责人: Sanjay Srivastava
• 金额: $ 32.78万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693804
• 关键词: 1,3-Butadiene; 2-butenal; ATF6 gene; Acceleration; Acrolein; Adipose tissue; Adult; Affect; Aldehydes; Animal Model; Apoptosis; Apoptotic; Atherosclerosis; Benzene; Biological; Biological Markers; Blood Vessels; Body Burden; Butadiene; Cardiometabolic Disease; Cardiovascular Physiology; Cardiovascular system; Carnosine; Cell physiology; Chemical Exposure; Chemical-Induced Change; Chemicals; Chronic Disease; Data; Deposition; Development; Diabetes Mellitus; Disease Resistance; Dose; Drug Metabolic Detoxication; Endoplasmic Reticulum; Endothelial Cells; Endothelium; Environmental Exposure; Environmental Impact; Exposure to; Fatty acid glycerol esters; Formaldehyde; Functional disorder; Funding; Glutathione; Goals; Hazardous Chemicals; Hazardous Substances; Health; Heart Diseases; Heart failure; Heat shock proteins; Hepatic; High Prevalence; Human; Hypertension; Individual; Inflammatory; Inhalation; Injury; Insulin Resistance; Investigation; Link; Lipid Peroxidation; Lipids; Measures; Mediating; Mediator; Metabolic; Metabolism; Molecular; Molecular Chaperones; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Nutritional status; Obesity; Oxidative Stress; Oxidative Stress Induction; Parents; Pathway interactions; Plasma; Platelet Activation; Poison; Process; Production; Property; Proteins; Protocols documentation; Reporting; Risk; Role; Signal Recognition Particle; Signal Transduction; Source; Stroke; Structure; Superfund; Surveys; Testing; Therapeutic; Tobacco smoke; Toxic effect; Trichloroethylene; Vinyl Chloride; Work; ambient air pollution; biomarker identification; cardiometabolic risk; cardiometabolism; cardiovascular health; cardiovascular injury; design; diet-induced obesity; disorder risk; endoplasmic reticulum stress; endothelial dysfunction; fatty liver disease; heart function; indexing; insight; insulin sensitivity; metabolomics; mouse model; novel; overexpression; pharmacologic; preclinical study; prevent; protein folding; protein misfolding; response; superfund site; synergism; systemic inflammatory response; therapeutic evaluation; therapy design; toxicant; urinary; vascular inflammation; vascular injury; volatile organic compound; western diet

SUMMARY Exposure to toxicants has been linked to the development or exacerbation of chronic disease. However, little is known about how volatile organic chemicals (VOC)—a class of toxicants associated with higher prevalence of type 2 diabetes (T2D) and stroke—promote the development of cardiometabolic disease (CMD). Accordingly, the overarching goals of this Superfund project are to determine the mechanisms by which VOCs negatively impact cardiovascular health and metabolism, identify biomarkers for VOC exposure and vascular injury, and test therapeutic strategies to minimize VOC-induced CMD. Our studies in the current funding cycle and preliminary data suggest that VOC such as benzene, vinyl chloride, and crotonaldehyde promote endoplasmic reticulum (ER) stress and trigger the unfolded protein response (UPR) in endothelial cells. Specifically, we hypothesize that aldehyde metabolites of VOC, which are generally more toxic than their parent compound, diminish endothelial toxicity by inducing ER stress, which triggers metabolic changes that accelerate ectopic lipid deposition and promote cardiometabolic dysfunction. To test this hypothesis we will: (1) examine the effects of VOC exposure on endothelial function and insulin resistance; (2) delineate the contribution of protein misfolding to the cardiometabolic toxicity of VOC. The design of these studies includes molecular and pharmacological interventions designed to detoxify or quench the reactive intermediates evoked by VOC exposure as well as studies that could lead to the identification of novel, sensitive and robust biomarkers of both VOC exposure and vascular injury. These studies were designed to synergize with and provide biological plausibility for the associations identified in Project 1. Successful completion of this project will lead to identification of the underlying cellular and molecular mechanisms by which VOC affect cardiometabolic function and provide insights into how VOC toxicity could be prevented or therapeutically minimized by targeting aldehydes or protein- folding pathways.

总结 接触有毒物质与慢性疾病的发展或恶化有关。然而， 了解挥发性有机化学品（VOC）-一类与高患病率相关的有毒物质 2型糖尿病（T2 D）和中风-促进心脏代谢疾病（CMD）的发展。因此，委员会认为， 这个超级基金项目的首要目标是确定挥发性有机化合物对环境产生负面影响的机制， 影响心血管健康和代谢，确定VOC暴露和血管损伤的生物标志物， 测试治疗策略，以尽量减少VOC诱导的CMD。我们在当前供资周期的研究， 初步数据表明，VOC，如苯，氯乙烯，巴豆醛促进内质网 内质网（ER）应激并触发内皮细胞中的未折叠蛋白反应（UPR）。我们特别 假设VOC醛类代谢物通常比其母体化合物毒性更大， 通过诱导ER应激减少内皮毒性，ER应激触发代谢变化，加速异位脂质 沉积并促进心脏代谢功能障碍。为了验证这一假设，我们将：（1）检查 VOC暴露对内皮功能和胰岛素抵抗的影响;（2）描述蛋白质错误折叠的贡献 VOC的心脏代谢毒性。这些研究的设计包括分子和药理学 旨在解毒或淬灭VOC暴露引起的活性中间体的干预措施，以及 研究可能导致识别新的，敏感的和强大的生物标志物的VOC暴露和 血管损伤这些研究被设计为与药物组合物协同作用并提供生物相容性。 项目1中确定的协会。该项目的成功完成将导致确定 VOC影响心脏代谢功能的潜在细胞和分子机制， 深入了解如何通过靶向醛类或蛋白质来预防或最大限度地减少VOC毒性， 折叠路径。