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.

概括接触毒物与慢性病的发生或恶化有关，但目前的研究还很少。了解挥发性有机化学物质 (VOC)——一类与较高流行率相关的有毒物质 2 型糖尿病 (T2D) 和中风——促进心脏代谢疾病 (CMD) 的发展。该超级基金项目的总体目标是确定 VOC 产生负面影响的机制影响心血管健康和新陈代谢，识别 VOC 暴露和血管损伤的生物标志物，以及测试治疗策略，以尽量减少 VOC 引起的 CMD 我们在当前资助周期中的研究和初步数据表明，苯、氯乙烯和巴豆醛等挥发性有机化合物可促进内质具体而言，我们研究了网状细胞（ER）应激并触发内皮细胞中的未折叠蛋白反应（UPR）。保留了 VOC 的醛类代谢物，其毒性通常比其母体化合物更高，通过诱导内质网应激来减少内皮毒性，内质网应激会引发代谢变化，加速异位脂质沉积并促进心脏代谢功能障碍为了检验这一假设，我们将：（1）检查以下因素的影响。 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；这些研究的设计包括分子和药理学。旨在解毒或淬灭 VOC 暴露引起的反应中间体以及这些研究可能会导致识别 VOC 暴露和这些研究旨在协同并提供生物学合理性。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潜在的细胞和分子机制深入了解如何通过针对醛或蛋白质来预防或治疗性最小化 VOC 毒性折叠路径。