Molecular Regulation of Atherosclerosis Regression

动脉粥样硬化消退的分子调控

• 批准号: 8434921
• 负责人: Edward A Fisher
• 金额: $ 61.9万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434921
• 关键词: Agonist; Algorithms; American; Anti-Inflammatory Agents; Anti-inflammatory; Aortic Segment; Apolipoprotein E; Arterial Fatty Streak; Atherosclerosis; Biology; Blocking Antibodies; Bone Marrow; Cells; Cerebrovascular Disorders; Cholesterol; Clinical; Collaborations; Coronary Arteriosclerosis; Coronary artery; DNA; Data; Elements; Emigrations; Environment; Foam Cells; Funding; Gene Expression; Gene Expression Profile; Gold; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; In Vitro; Individual; Inflammatory; Institutes; Knock-in Mouse; Lasers; Lead; Learning; Lipids; Literature; Measures; Messenger RNA; Meta-Analysis; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Nuclear Hormone Receptors; Nucleic Acid Regulatory Sequences; Pathway interactions; Phenotype; Plasma; Plasmids; Population; Process; Promoter Regions; Property; Proteomics; Regulation; Regulatory Element; Reporter; Reporting; Residual state; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Small Interfering RNA; Sterols; Study models; System; Systems Biology; Technology; Testing; Therapeutic; Time; Transcriptional Regulation; Transfection; Transgenic Organisms; Transplantation; United States National Institutes of Health; Up-Regulation; Wild Type Mouse; aortic arch; base; biological systems; chemokine receptor; chromatin immunoprecipitation; cis acting element; in vivo; inflammatory marker; knock-down; lymph nodes; macrophage; migration; monocyte; mouse model; novel; novel diagnostics; novel therapeutics; optimism; promoter; public health relevance; research study; reverse cholesterol transport; tool; validation studies

DESCRIPTION (provided by applicant): The ultimate treatment for coronary artery disease is the regression of the underlying atherosclerotic process. We have developed a novel mouse model for the study of regression in which plaques that developed into apoE-/- mice (high plasma non-HDL cholesterol (C), low HDL-C, absent apoE) are transplanted into wild type (WT) mice, which have low non-HDL-C, normal HDL-C, and normal apoE in their plasma. We have found that in the WT plasma environment, there is remarkable remodeling of the transplanted plaques over a relatively short time, with depletion of the majority of CD68+ cells (which are primarily macrophages and foam cells). Previous studies in WT recipients showed that the depletion of CD68+ cells reflected their emigration to lymph nodes, and required the upregulation of their chemokine receptor CCR7, a known migratory factor in monocyte-derived cells. Furthermore, the phenotypic state of the CD68+ cells shifted from an inflammatory ("M1") to an anti-inflammatory one ("M2"). We hypothesize that each of the 3 plasma changes in the WT recipient contributes to the migratory and inflammatory properties of plaque CD68+ cells during regression. Because each plasma change promotes reverse cholesterol transport (RCT), a related hypothesis is that deficiency in macrophage RCT will compromise the ability of a plasma factor to influence CD68+ cell emigration and polarization to the M2 state. Two other hypotheses are that the transcriptional regulation of the migration factor CCR7 is regulated by the nuclear hormone receptor LXR and the sterol-regulated SREBP pathway (based on preliminary studies), and that the identification of the molecular processes central to the regression process in plaque CD68+ cells requires a systems biology approach that includes the meta- analyses of microarray and proteomic data across in vivo and in vitro studies. To test these hypotheses, there are 3 aims. Aim 1: To establish the roles of changes in plasma non-HDL-C, HDL-C, and apoE, and of RCT in atherosclerosis regression and phenotypic changes in plaque CD68+ cells; Aim 2: To determine the roles of LXR and SREBP in regulating CCR7 expression in vitro and in vivo; Aim 3: To employ a systems biology approach to identify the key molecular drivers of regression.

描述（由申请人提供）：冠状动脉疾病的最终治疗方法是基础动脉粥样硬化过程的回归。我们已经开发了一种新型的小鼠模型来研究回归，其中将斑块发展为APOE - / - 小鼠（高血浆非HDL胆固醇（C），低HDL-C，HDL-C，不存在APOE）被移植到野生型（WT）小鼠中，这些小鼠在其plasma中具有低非HDL-C，正常的HDL-C，正常HDL-C和正常APOE。我们发现，在WT血浆环境中，在相对较短的时间内，移植斑块的重塑显着，大多数CD68+细胞（主要是巨噬细胞和泡沫细胞）的耗竭。先前在WT受体中的研究表明，CD68+细胞的耗竭反映了它们的迁移到淋巴结，并且需要上调其趋化因子受体CCR7，这是单核细胞衍生细胞中已知的迁移因子。此外，CD68+细胞的表型状态从炎症（“ M1”）转变为抗炎剂（“ M2”）。我们假设WT受体中的3个血浆中的每一个都会在回归过程中有助于斑块CD68+细胞的迁移和炎症特性。因为每种血浆变化都会促进反向胆固醇转运（RCT），所以一个相关的假设是，巨噬细胞RCT的缺乏将损害血浆因子影响CD68+细胞移民和极化对M2状态的能力。其他两个假设是，迁移因子CCR7的转录调节受核激素受体LXR的调节和固醇调节的SREBP途径（基于初步研究），并且分子过程的鉴定在斑块CD68+细胞中涉及的分析中的分析中核心的识别，该过程包括plaque cd68+细胞分析的元素分析。和体外研究。为了检验这些假设，有3个目标。目标1：确定血浆非HDL-C，HDL-C和APOE的变化以及RCT在动脉粥样硬化回归中的RCT和斑块CD68+细胞的表型变化的作用；目标2：确定LXR和SREBP在体外和体内调节CCR7表达中的作用；目标3：采用系统生物学方法来识别回归的关键分子驱动因素。