Epidemiology of Vascular Inflammation & Atherosclerosis

描述（申请人提供）：目前，关于动脉粥样硬化的主流假设是，它主要由两个独立的途径驱动：高脂血症（“刺激”）和炎症（“反应”）。虽然血管细胞介导炎症对动脉粥样硬化的影响，但对血管细胞流行病学和血管细胞表型与动脉粥样硬化的关系知之甚少。我们的主要假设是血管细胞生物学的变异与动脉粥样硬化的群体变异有关。为了探索这一假设，我们建议使用大型流行病学研究MESA（多种族动脉粥样硬化研究）的1000人样本，其中已经收集了冠状动脉钙化，颈动脉壁厚度和其他动脉粥样硬化的估计。在Specific Aim 1中，我们建议确定新的细胞表型，并确定它们的分布和与动脉粥样硬化的横断面关联。我们将研究：先天免疫反应（单核细胞激活，以组织因子表达为标记，基于三种激动剂的刺激；自然杀伤细胞计数和γ - δ T细胞计数）；适应性免疫反应（Th1和Th2辅助性T细胞和记忆T细胞的分布）和血管完整性（循环内皮祖细胞）。在Specific Aim 2中，我们建议测量与这些细胞表型相关的血浆成分，包括IgG亚类分布、IgE、热休克蛋白和Ox-LDL抗体、IL-10和内皮蛋白C受体；并确定这些指标以及MESA数据集中的其他炎症指标与细胞表型和动脉粥样硬化之间的关系。在Specific Aim 3中，我们建议开发用于流行病学的先进分子和细胞表型，并开始应用，如IgG亚类特异性抗ox -LDL抗体，单核细胞crp介导的LDL摄取，T细胞受体依赖性γ - δ T细胞亚群，T细胞和单核细胞细胞因子表达谱。我们认为，阐明炎症相关通路的表型变异及其对动脉粥样硬化的影响至关重要，这样我们就可以更好地理解病理生理学，开发更好的风险评估方法，并产生更有效的干预措施。此外，这些新的表型将被证明是有用的中间表型，为未来研究遗传变异在人类生物学和疾病中的作用。

DESCRIPTION (provided by applicant): Currently, the predominant hypothesis regarding atherosclerosis is that it is in major part driven by two independent pathways: hyperlipidemia (the "stimulation") and inflammation (the "response"). Although vascular cells mediate the influence of inflammation on atherosclerosis, very little is known about vascular cell epidemiology and the relationship of vascular cell phenotypes to atherosclerosis. Our main hypothesis is that variation in vascular cell biology is related to the population variation in atherosclerosis. To explore this hypothesis, we propose to use samples from a 1000-person subset of the large epidemiological study MESA (Multi-Ethnic Study of Atherosclerosis) in which coronary calcification, carotid wall thickness, and other estimates of atherosclerosis have already been collected. In Specific Aim 1 we propose to ascertain new cellular phenotypes and determine their distributions and cross-sectional associations with atherosclerosis. We will study: the innate immune response (monocyte activation using as a marker Tissue Factor expression, based on stimulation with three agonists; Natural Killer cell counts, and gamma-delta T cell counts); the adaptive immune response (distributions of Th1 and Th2 T Helper cells, and memory T cells), and vessel integrity (circulating endothelial progenitor cells). In Specific Aim 2 we propose to measure plasma constituents related to these cellular phenotypes, including IgG subclass distribution, IgE, antibodies to Heat Shock proteins and Ox-LDL, IL-10, and Endothelial Protein C Receptor; and to determine the relationship of these measures, plus other inflammation measures in the MESA dataset, to both the cellular phenotypes and atherosclerosis. In Specific Aim 3 we propose to develop for epidemiological use, and begin to apply, advanced molecular and cellular phenotypes such as IgG subclass-specific anti-Ox-LDL antibodies, monocyte CRP-mediated LDL uptake, T Cell Receptor-dependent gamma-delta T Cell subsets, and T cell and monocyte cytokine expression profiles. We believe it is critical to elucidate the phenotypic variation in inflammation-related pathways and the contribution of this variation to atherosclerosis, so that we may better understand the pathophysiology, develop better methods for assessing risk, and produce more effective interventions. In addition, these new phenotypes will prove useful as intermediate phenotypes for future studies of the role of genetic variation in human biology and disease.