Cardiovascular Effects of Particles:The Role of Oxidative Stress and Metal Pathw

描述（由申请人提供）：自20世纪80年代末以来，对急性和慢性暴露于颗粒空气污染的研究表明，它与早期死亡有关。很快就发现，这些早死的人大多数是心血管疾病。美国国家研究委员会确定的研究重点包括：确定可能解释与暴露于环境颗粒有关的心脏死亡率/发病率的流行病学调查结果的潜在机制，确定颗粒物质对健康不良后果风险增加的亚人群，以及了解不同类型颗粒的不同毒性。我们拟利用退伍军人管理局在大波士顿地区开展的一项前瞻性队列研究“规范老龄化研究”的数据，沿着机械途径研究不同类型和来源的颗粒暴露与心血管和肺部反应之间的关系。具体来说，我们将研究以心率变异性为指标的自动功能的短期变化是否与颗粒暴露有关，并通过检测基因型对氧化应激和金属处理防御的影响修饰，确定这种影响是否部分由氧化应激和金属毒性介导。我们将同样地检查血管功能的关联和效果修改，通过无创动脉适应性和血压的脉冲多普勒测量指标，并检查与炎症和氧化应激的全身标志物（c反应蛋白、Sicam、Svcam、同型半胱氨酸和8-羟基鸟苷）的直接关联。

DESCRIPTION (provided by applicant): Since the late 1980s, studies of acute and chronic exposure to particulate air pollution have shown it to be associated with early death. It was quickly apparent that most of these early deaths were from cardiovascular disease. Definition of the underlying mechanisms that may explain the epidemiological findings of cardiac mortality/morbidity associated with exposure to ambient particles, definition of subpopulation at increased risk of adverse health outcomes from particulate matter, and understanding the differential toxicity of different types of particles are among the research priorities defined by the U. S. National Research Council. We propose to examine the association of different types and sources of particle exposure with cardiovascular and pulmonary responses along a mechanistic pathway, using data from the Normative Aging Study, a prospective cohort study conducted by the Veterans Administration in the greater Boston area. Specifically, we will examine whether short term changes in automatic function, as indexed by heart rate variability, are associated with particle exposure, and determine whether that effect is mediated by part by oxidative stress and metal toxicity by examining effect modification by genotypes that modify defenses against oxidative stress and metal handling. We will similarly examine associations, and effect modification, for vascular function, as indexed by a non-invasive pulse Doppler measures of arterial compliance and blood pressure, and examine a direct association with systemic markers of inflammation and oxidative stress (c reactive protein, Sicam, Svcam, homocysteine, and 8-hydroxyguanosine.