Identifying the Molecular Mechanisms of Air Pollution-Induced Thrombosis

确定空气污染诱发血栓形成的分子机制

基本信息

批准号：
10440411
负责人：
Eva Vitucci
金额：
$ 1.3万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10440411
关键词：
ATF2 gene Adverse effects Air Air Pollution Alveolar Anticoagulants Antioxidants Automobile Driving Binding Biological Assay Biosensor Blood Coagulation Factor Blood capillaries Cardiovascular Diseases Cardiovascular system Cessation of life Chromatin Coagulation Process Coronary heart disease Cysteine Data Deposition Development Diesel Exhaust Distal Endothelial Cells Endothelium Epithelial Epithelial Cells Exposure to FOS gene Fibrin Fibrinolysis Fibroblasts Functional disorder Future Gene Expression Generations Genes Genetic Glutathione Goals Heart Rate Homeostasis Hydrogen Peroxide Impairment In Vitro Intervention Studies JUN gene Kinetics Link Lung MAP Kinase Gene MAPK Signaling Pathway Pathway MAPK8 gene Mediating Mediator of activation protein Modeling Molecular Oxidation-Reduction Oxidative Stress Particulate Particulate Matter Pathology Pathway interactions Phenotype Platelet Activation Play Populations at Risk Prevention strategy Principal Investigator Production Promoter Regions Proteins RNA Role Shapes Signal Pathway Signal Transduction Stroke Testing Therapeutic Thrombin Thrombosis Time Training Vascular Endothelial Cell Vascular Endothelium Work activating transcription factor alveolar epithelium catalase-polyethylene glycol cell type chromatin immunoprecipitation in vitro Model in vivo lung microvascular endothelial cells mortality novel oxidation p38 Mitogen Activated Protein Kinase p65 prevent promoter systemic inflammatory response thrombotic transcription factor treatment strategy vascular bed

项目摘要

Project Summary: Particulate matter (PM) air pollution is a common promoter for the development of thrombosis and cardiovascular disease. Specifically, exposure and deposition of PM in the alveolar capillary region (ACR) of the lung promotes thrombosis through platelet activation, impaired fibrinolysis, and increased coagulation factor production; however, the molecular mechanisms producing these adverse effects following PM exposure remain unclear. Our goal is to identify the vascular endothelium's role in promoting these thrombotic effects and elucidate the molecular mechanisms that result in a pro-thrombotic endothelium. To do this we have developed an organotypic in vitro model of the ACR in which we expose alveolar epithelial cells within the model to PM and determine the trans-epithelial (TE) effect in the underlying endothelial cells within the model. Our preliminary data suggests this TE exposure induces endothelial redox dysfunction, decreases the expression of anti-coagulant and fibrinolytic genes, and increases the expression of procoagulant genes. Our central hypothesis is TE exposure-induced redox dysfunction activates a pro-thrombotic endothelium by alternatively regulating the NF-κB and MAPK pathways. To test this hypothesis, our first aim is to define the relationship between the induced endothelial redox dysfunction and the activation of a pro-thrombotic endothelium. To define this relationship, we will compare the kinetics of redox dysfunction with the temporal expression of pro-thrombotic targets identified in our preliminary data and with the kinetics of functional thrombotic endpoints. Antioxidant intervention studies will then be performed to determine whether TE exposure-induced redox dysfunction drives the activation of a pro- thrombotic endothelium. Our second aim is to determine how the NF-κB and MAPK signaling pathways activate a thrombotic endothelium following a TE exposure. To determine these pathways' role we will evaluate the activation of the NF-κB, c-Jun N-terminal kinase (JNK), and p38 signaling pathways and will assess promoter binding at the activated pro-thrombotic targets of the downstream transcription factors of these pathways, p65, c-Fos/c-Jun, and ATF-2. Antioxidant intervention studies will then be performed to determine if TE-induced redox dysfunction mediates the activation of a pro-thrombotic endothelium by alternatively regulating these cellular pathways. The molecular mechanisms identified upon completion of these aims will help elucidate the vascular endothelium's role in promoting PMI-thrombosis. With these results, preventative and therapeutic strategies against PMI-thrombosis and related cardiovascular diseases can be developed. Completion of these aims will advance my training as a molecular toxicologist and support my development into a successful principal investigator.

项目概要：颗粒物 (PM) 空气污染是血栓形成和心血管疾病发生的常见促进因素具体来说，PM 在肺泡毛细血管区域 (ACR) 的暴露和沉积会促进疾病。血小板活化、纤维蛋白溶解受损和凝血因子产生增加导致血栓形成；然而，PM 暴露后产生这些不利影响的分子机制仍不清楚。我们的目标是确定血管内皮在促进这些血栓形成效应中的作用并阐明导致促血栓内皮的分子机制为此，我们开发了一种器官型。 ACR 的体外模型，其中我们将模型内的肺泡上皮细胞暴露于 PM 并确定我们的初步数据表明了模型内底层内皮细胞的跨上皮（TE）效应。 TE 暴露诱导内皮氧化还原功能障碍，降低抗凝剂和纤溶剂的表达基因，并增加促凝血基因的表达我们的中心假设是 TE 暴露诱导。氧化还原功能障碍通过交替调节 NF-κB 和 MAPK 激活促血栓内皮为了检验这一假设，我们的首要目标是定义诱导内皮细胞之间的关系。为了定义这种关系，我们将比较氧化还原功能障碍和促血栓内皮的激活。氧化还原功能障碍的动力学与我们在我们的研究中确定的促血栓目标的时间表达初步数据和功能性血栓形成终点的动力学研究将进行。然后进行以确定 TE 暴露引起的氧化还原功能障碍是否会驱动亲- 我们的第二个目标是确定 NF-κB 和 MAPK 信号通路如何激活。为了确定这些途径的作用，我们将评估 TE 暴露后的血栓内皮。激活 NF-κB、c-Jun N 末端激酶 (JNK) 和 p38 信号通路，并将评估启动子结合这些途径的转录下游因子 p65 的激活的促血栓形成靶标，然后将进行 c-Fos/c-Jun 和 ATF-2 干预研究，以确定 TE 是否诱导氧化还原。功能障碍通过交替调节这些细胞来介导促血栓内皮的激活完成这些目标后确定的分子机制将有助于阐明血管。内皮细胞在促进 PMI 血栓形成中的作用根据这些结果，我们提出了预防和治疗策略。可以开发针对 PMI 血栓形成和相关心血管疾病的药物。我作为分子毒理学家的培训促进并支持我发展成为一名成功的校长研究者。