Role and Regulation of CCR7 in Regression of Atherosclerotic Lesions

CCR7 在动脉粥样硬化病变消退中的作用和调节

基本信息

批准号：
7580951
负责人：
Jonathan E Feig
金额：
$ 4.62万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-12 至 2011-02-11
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7580951
关键词：
Acute Acute myocardial infarction Address Age Aging Agonist Agreement American American Heart Association Animal Model Apolipoprotein E Apolipoproteins Arterial Fatty Streak Atherosclerosis Biology Blood Vessels Breslow Thickness CCL19 gene CCL21 gene Cardiac Cause of Death Cell Culture Techniques Cell Line Cells Cessation of life Cholesterol Clinical Clinical Trials Coronary Arteriosclerosis Data Dendritic Cells Development Diffuse Disease Disease Progression Doctor of Philosophy Dyslipidemias Eko Elderly Emigrations Event Foam Cells Functional disorder Gene Expression Genetic Goals Head Health Heart Diseases High Density Lipoproteins Human Hyperlipidemia In Vitro Infusion procedures Intervention Investigation Knockout Mice LDL Cholesterol Lipoproteins Lasers Lead Lesion Ligands Link Longevity Low-Density Lipoproteins Mechanics Mediating Mediator of activation protein Messenger RNA Microscopy Minor Planets Modeling Molecular Mus Myocardial Infarction Nature Older Population Operative Surgical Procedures Pathway interactions Patients Pharmaceutical Preparations Physiological Plague Plasma Population Process Proteins Protocols documentation Public Health Publishing Regulation Reporting Research Risk Role Rupture Stroke Techniques Testing Therapeutic Agents Time Tissues Transgenic Mice Transplant Recipients Transplantation Up-Regulation Wild Type Mouse Work acute coronary syndrome age group age related aging population cardiovascular disorder risk cell motility cell type chemokine receptor high risk in vivo lymph nodes member monocyte neutralizing antibody novel research study restoration statistics tool

项目摘要

DESCRIPTION (provided by applicant): Coronary artery disease (CAD), the direct result of atherosclerosis, is the most common cause of death in people over the age of 65. Although, statins have been used to lower LDL and retard disease progression, these drugs have modest impact on lesion burden as reflected by the degree of regression seen in the REVERSAL and recent ASTEROID studies and the still substantial rates of heart attacks in large-scale clinical trials of these drugs. By understanding the factors that lead to plaque regression, better treatment options may be developed for many at risk, especially the older population, who already carry a heavy plaque burden. My supervisor, Dr. Edward Fisher, has led the development of in-vivo regression models using surgical and genetic approaches to the standard models of atherosclerosis progression. Using laser capture microscopy to capture foam cells, important mediators in plaque pathophysiology, we studied gene expression changes specifically in these cells in plaques. We showed that CCR7, an established maturation marker for dendritic cells that promotes their emigration from tissues to lymph nodes, was functionally required to promote regression in intermediate lesions, the type that most resembles the ones most prone to rupture and cause an acute myocardial infarction in people. Since members of the aging population with CAD have these lesions, we propose to 1) establish the functional requirement for CCR7 in regression by using a different in vivo approach and 2) determine the molecular mechanisms inducing CCR7 gene expression. Ultimately, the results obtained from the proposed studies may represent a novel path towards achieving regression of atherosclerosis in the aging, a population expanding due to the average life-span increasing. Coronary artery disease (CAD), the direct result of atherosclerosis, is an age-related disorder with a tremendous impact on public health. Although retarding the progression is important, this will not eliminate the huge plaque burden already present in the elderly. With regression models and the tools to analyze them on a molecular level, there is the exciting potential to identify factors that can be manipulated to accelerate regression in patients at risk for CAD, most of whom are members of the older population.

描述（由申请人提供）：冠状动脉疾病（CAD）是动脉粥样硬化的直接结果，是65岁以上人的最常见死亡原因。尽管如此，他汀类药物被用来降低LDL和延迟疾病的进展，但这些药物对狮病的负担进行了适度的影响，这是在较大的反复试验中所反映的，并且在反复研究中的攻击程度很大，并且是反向研究的次数。这些药物。通过了解导致斑块回归的因素，可能会针对许多处于危险中的人，尤其是已经承受着沉重的斑块负担的老年人的危险中。我的主管爱德华·费舍尔（Edward Fisher）博士利用手术和遗传方法为动脉粥样硬化进展的标准模型领导了体内回归模型的发展。使用激光捕获显微镜捕获泡沫细胞，斑块病理生理学中的重要介质，我们研究了斑块中这些细胞中特异性变化的基因表达变化。我们表明，CCR7是树突状细胞已建立的成熟标记，促进其从组织到淋巴结的迁移是在功能上需要促进中间病变的回归的，这种类型最类似于那些最容易破裂和引起急性心肌梗死的人。由于具有CAD的老化人群的成员具有这些病变，因此我们建议1）通过使用不同的体内方法和2）确定诱导CCR7基因表达的分子机制来确定CCR7在回归中的功能要求。最终，从提出的研究中获得的结果可能代表了实现衰老动脉粥样硬化消退的新途径，这是由于平均寿命增加而扩大的人群。冠状动脉疾病（CAD）是动脉粥样硬化的直接结果，是一种与年龄有关的疾病，对公共卫生有巨大影响。尽管延迟进展很重要，但这并不能消除老年人已经存在的巨大牌匾负担。借助回归模型和以分子水平分析它们的工具，有令人兴奋的潜力可以识别可以操纵的因素，以加速有CAD风险的患者的回归，其中大多数是老年人群的成员。