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，它是由两种独立途径驱动的主要部分：高脂血症（“刺激”）和炎症（“反应”）。尽管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以及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种群变异有关。为了探讨这一假设，我们建议使用大型流行病学研究台面1000人子集的样品（动脉粥样硬化的多种族研究），其中冠状动脉钙化，颈动脉壁的厚度和其他动脉粥样硬化的估计已经收集。在特定目标1中，我们建议确定新的细胞表型，并确定其分布和与动脉粥样硬化的横截面关联。我们将研究：先天免疫反应（基于三种激动剂刺激；自然杀伤细胞计数和伽马 - 戴尔塔T细胞计数的刺激，单核细胞激活作为标记组织因子表达）；适应性免疫反应（Th1和Th2 T辅助细胞的分布以及记忆T细胞的分布）以及血管完整性（循环内皮祖细胞）。在特定目标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，热休克蛋白的抗体和OX-LDL，IL-10和内皮蛋白C受体；并确定这些措施的关系，以及梅萨数据集中的其他炎症度量与细胞表型和动脉粥样硬化的关系。在特定的目标3中，我们建议开发用于流行病学的使用，并开始应用高级分子和细胞表型，例如IgG亚类特异性抗OX-OX-LDL抗体，单核细胞CRP介导的LDL摄取，T细胞受体受体依赖性γ-Delta T细胞和T细胞和T细胞和单核cytokyte Cytokyte Cytokyte Cytokyte cytokyte cytokyte cytokokyte cytokyte cytokycytokycytokycy。我们认为，阐明与炎症相关途径的表型变化以及这种变异对动脉粥样硬化的贡献至关重要，以便我们可以更好地了解病理生理学，开发出更好的评估风险方法，并产生更有效的干预措施。此外，这些新表型将被证明是中间表型，用于将来研究遗传变异在人类生物学和疾病中的作用。