PM2.5 from Fracking Operations Induces Microvascular and Mitochondrial Dysfunction

页岩气生产，水平井和水力压裂井的开发 技术，是美国经济的主要驱动力。从准备井垫到完井的过程 这项研究创造了一种复杂的空气传播毒物混合物，其中包括高浓度的颗粒物- 柴油发动机排气中的TER(PM)、超细颗粒物(UFP)、二氧化硅以及挥发性有机化合物。 来自地质、地表和人为来源的重金属(VOCs)和多环芳烃。致- 个人接触到的材料的质量令联邦、州和地方政府机构感到震惊- 概念化。事实上，靠近非常规天然气开发(UNGD)井场的社区 与没有联合国开发计划署的社区相比，对健康的影响更大。然而，尚不清楚的是，Ac-Ac是如何- 积极的UNGD加速了这些健康影响。PM，特别是细PM(直径2.5微米，PM2.5)是已知的 心血管毒物。一些研究表明，在血管和微血管方面存在显著的损害。 血管功能。总而言之，这些研究表明，即使在低血糖的情况下，也会对心血管健康产生显著影响。 急诊室水平。此外，我们还发现心肌线粒体受损，这是疾病进展的一个重要因素。 暴露在空气中的PM引起的心力衰竭。然而，尚不清楚的是特定药物的相对毒性 肺PM2.5博览会后心血管损伤的来源(来源解析)或机制- 好的。长期目标是建立解释流行病学健康问题的生理学机制。 UNGD期间的燕鸥。R15应用的目标是大幅推进科学理解- ING研究了将肺部UNGD PM2.5与远端组织功能障碍联系起来的机制。中心假设是 在水力压裂过程中现场收集的PM2.5肺暴露将有更大的微血管 线粒体功能障碍，其特征是支持正常小动脉连接的机制紊乱。 狭窄、内皮依赖性扩张、线粒体功能和促凋亡蛋白表达 心功能下降。这一假说将通过以下方式得到验证：1)确定MI中的机械性变化。 UNGD不同阶段的微血管和线粒体功能：2)确定心功能 由于微血管和线粒体功能障碍而导致的衰退。这项工作的基本原理是亲- 已提出的研究将大大增加对PM2.5诱导的微血管和有丝分裂的机制的洞察。 软骨症，同时支持我们教育和准备学生的使命。利用学生进行测试 这些目标将使学生获得显微镜、尸检、解剖学、生物化学和 微血管和心血管生理学。提出的这项研究具有创新性，因为它直接阻止- 《联合国全球消除对妇女一切形式歧视》三个阶段产生的全部毒物的地雷毒性。建议的重行- 搜索具有重要意义，因为它将评估钻井不同阶段的心血管毒性以及机械-机械- 将弥合基础科学和流行病学UNGD健康影响之间的差距的功能障碍。

The production of shale gas, and the development of wells using horizontal drilling and hydraulic fracturing technology, is a major driver of the U.S. economy. The process of preparing well pads to completion of the work creates a complex mixture of airborne toxicants that includes elevated concentrations of particulate mat- ter (PM), ultrafine particles (UFPs) from diesel engine exhaust (DEE), silica, as well as volatile organic com- pounds (VOCs) and polyaromatic hydrocarbons from geological, surface and anthropogenic sources. The to- tality of materials that the individuals are exposed to is alarming to federal, state and local governmental organ- izations. Indeed, communities that are proximal to unconventional natural gas development (UNGD) well sites have greater health effects compared to communities without UNGD. However, what is not known is how ac- tive UNGD precipitates these health effects. PM, specifically fine PM (<2.5 µm in diameter, PM2.5) is a known cardiovascular toxicant. Several studies have demonstrated a significant impairment in vascular, and micro- vascular function. Combined, these studies indicate significant cardiovascular health effects even at low ambi- ent levels. Moreover, we have shown cardiac mitochondrial impairment, a significant contributor to progression of heart failure, following ambient PM exposure. However, what is not known is the relative toxicity of specific sources (source apportionment) or the mechanisms of cardiovascular injury following pulmonary PM2.5 expo- sure. The long-term goal is to establish physiologic mechanisms that explain the epidemiological health pat- terns during UNGD. The objective for this R15 application is to substantially advance the scientific understand- ing of the mechanisms that link pulmonary UNGD PM2.5 to remote tissue dysfunction. The central hypothesis is that pulmonary exposure to PM2.5 collected on-site during hydraulic fracturing will have greater microvascular and mitochondrial dysfunction, characterized by disturbances in mechanisms supporting normal arteriolar con- striction, endothelium-dependent dilation, mitochondrial function, and pro-apoptotic protein expression leading to cardiac functional declines. This hypothesis will be tested by 1) identifying the mechanistic alterations in mi- crovascular and mitochondrial function during different stages of UNGD, 2) identifying the cardiac functional declines that result from microvascular and mitochondrial dysfunction. The rationale for this work is that pro- posed research will add substantially to the mechanistic insights of PM2.5-induced microvascular and mito- chondrial dysfunction, while supporting our mission to educate and prepare students. Utilizing students to test theses aims will allow the students to gain knowledge in microscopy, necropsy, anatomy, biochemistry, and microvascular and cardiovascular physiology. The research proposed is innovative because it directly deter- mines toxicity of the complete matrix of toxicants produced during three phases of UNGD. The proposed re- search is significant as it will assess cardiovascular toxicity during different phases of drilling as well as mech- anisms of dysfunction that will bridge the gap between basic science and epidemiological UNGD health effects.