Epidemiology of Vascular Inflammation & Atherosclerosis

血管炎症的流行病学

• 批准号: 7080425
• 负责人: RUSSELL P TRACY
• 金额: $ 35.04万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7080425
• 关键词: T lymphocyte; antibody; atherosclerosis; blood vessels; cardiovascular disorder epidemiology; cell biology; cell population study; clinical research; cytokine; helper T lymphocyte; human data; immune response; immunity; immunoglobulins; inflammation; interleukin 10; leukocyte activation /transformation; low density lipoprotein; monocyte; oxidized lipid; phenotype; plasma; stem cells; vascular endothelium

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.

描述（由申请人提供）：目前，关于动脉粥样硬化的主要假设是，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化与动脉粥样硬化的群体变化有关。为了探讨这一假设，我们建议使用来自大型流行病学研究梅萨（动脉粥样硬化多种族研究）的1000人亚组的样本，其中冠状动脉钙化，颈动脉壁厚度和其他动脉粥样硬化的估计已经收集。在具体目标1中，我们建议确定新的细胞表型，并确定其分布和横截面与动脉粥样硬化的关联。我们将研究：先天性免疫应答（基于三种激动剂的刺激，使用组织因子表达作为标志物的单核细胞活化;自然杀伤细胞计数和γ-δ T细胞计数）;适应性免疫应答（Th 1和Th 2 T辅助细胞和记忆T细胞的分布）和血管完整性（循环内皮祖细胞）。在具体目标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、热休克蛋白抗体和Ox-LDL、IL-10和内皮蛋白C受体;并确定这些指标以及梅萨数据集中的其他炎症指标与细胞表型和动脉粥样硬化的关系。在具体目标3中，我们建议开发并开始应用先进的分子和细胞表型用于流行病学用途，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细胞亚群以及T细胞和单核细胞因子表达谱。我们认为，阐明炎症相关通路中的表型变异以及这种变异对动脉粥样硬化的贡献至关重要，这样我们就可以更好地了解病理生理学，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，为未来的研究在人类生物学和疾病的遗传变异的作用。