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

基本信息

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
项目类别：
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

项目摘要

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.

概括暴露于毒物与慢性疾病的发展或加剧有关。但是，几乎没有知道挥发性有机化学（VOC）的了解 2型糖尿病（T2D）和中风 - 心脏代谢疾病（CMD）的发展。根据这个超级基金项目的总体目标是确定VOC负面的机制影响心血管健康和新陈代谢，确定VOC暴露和血管损伤的生物标志物，以及测试理论策略以最大程度地减少VOC诱导的CMD。我们在当前资金周期中的研究初步数据表明，苯，氯化乙烯基和克罗替醛等VOC促进内质网状（ER）应力并触发内皮细胞中展开的蛋白质反应（UPR）。具体来说，我们假设VOC的醛代谢物通常比其母体化合物更具毒性，通过诱导ER应力降低内皮毒性，这会触发代谢变化，使生态脂质加速沉积和促进心脏代谢功能障碍。为了检验该假设，我们将：（1）检查内皮功能和胰岛素抵抗的VOC暴露；（2）描述蛋白质错误折叠的贡献对VOC的心脏代谢毒性。这些研究的设计包括分子和药物旨在排毒或淬灭的干预措施可能导致VOC暴露和新颖，敏感和健壮的生物标志物和强大的生物标志物的研究血管损伤。这些研究旨在协同并为生物学合理性项目1中确定的协会。该项目的成功完成将导致确定 VOC影响心脏代谢功能并提供的基本细胞和分子机制通过靶向醛或蛋白质 - 折叠路径。