Role of Retroelements in Environmental Atherogenesis

逆转录因子在环境动脉粥样硬化形成中的作用

• 批准号: 7740689
• 负责人: Kenneth S. Ramos
• 金额: $ 37万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-26 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7740689
• 关键词: Actins; Address; Air; Area; Aromatic Polycyclic Hydrocarbons; Arterial Fatty Streak; Arteries; Atherosclerosis; Benzo(a)pyrene; Biological; Blood; Blood Vessels; Brain; Carcinogens; Cardiovascular system; Cell Line; Cells; Chemicals; Chickens; Cholesterol; Chronic; Clinical; Code; Colon; Cytochrome P450; Cytomegalovirus; DNA Damage; Developed Countries; Development; Diabetes Mellitus; Disease; Disease Progression; Enhancers; Environmental Pollution; Epigenetic Process; Excision; Exposure to; Extracellular Matrix; Family member; Gene Expression; Genes; Genetic; Genetic Programming; Genomic Instability; Genomics; Goals; Heart; Human; Hydrocarbons; Hypertension; In Vitro; Incidence; Infiltration; Inflammatory; Injury; Investigation; Kidney; L1 Elements; Laboratories; Lesion; Limb structure; Liver; Mediating; Metabolism; Molecular; Molecular Target; Monitor; Morbidity - disease rate; Mus; Names; Nature; Nuclear; Nucleic Acid Regulatory Sequences; Onset of illness; Organ; Oxidation-Reduction; Oxidative Stress; Pancreas; Particulate; Particulate Matter; Paste substance; Pattern; Phenotype; Pollution; Primates; Proteins; RNA; RNA Polymerase II; RNA-Directed DNA Polymerase; Recommendation; Research; Retroelements; Retrotransposition; Risk Factors; Rodent; Role; Severities; Signal Transduction; Smoking; Smooth Muscle Myocytes; Somatic Cell; Specificity; Staging; System; T-Lymphocyte; Tail; Testing; Testis; Tissues; Tobacco smoke; Transcript; Transcriptional Activation; Transgenes; Transgenic Mice; Up-Regulation; Vascular Diseases; Virus; atherogenesis; base; c-Ha-ras Gene; cell type; cis acting element; endonuclease; environmental chemical; feeding; in vivo; interest; macrophage; mortality; mouse model; overexpression; promoter; public health relevance; recombinase; research study; response; unpublished works; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Atherosclerosis, the leading cause of morbidity and mortality in industrialized nations, is a fibro-proliferative disease associated with endothelial injury, recruitment of inflammatory cells (macrophages and T cells), expansion of vascular smooth muscle cells (vSMCs) and buildup of cholesterol and extracellular matrix within the inner lining of arteries. Clinical disease results from occlusion of vessels that feed the heart, brain, or extremities. The early stages of atherosclerosis (atherogenesis) involve inflammatory injury to the vessel wall, infiltration of macrophages and uncontrolled proliferation of vSMCs. Oxidative injury to the vessel wall is a common denominator of the atherogenic response, with elevated levels of blood cholesterol, high blood pressure, diabetes, and smoking recognized as primary risk factors. Chronic exposures to air particulates and chemicals associated with particulate matter, such as polycyclic aromatic hydrocarbons, have been associated with development or exacerbation of atherosclerosis in rodents and primates. Of relevance are the biological effects of benzo(a)pyrene (BaP), a carcinogen present in various forms of pollution and metabolized by cytochromes P450 to intermediates that damage DNA and cause oxidative stress. Repeated exposure of vSMCs to BaP in vivo or in vitro induces atherosclerotic changes within the vascular wall. The molecular mechanisms responsible for BaP atherogenesis involve transcriptional deregulation of gene expression and DNA damage. Of interest are responses involving activation of the c-Ha-ras gene and long interspersed nuclear elements (LINE 1 or L1) in human and murine vSMCs. L1s have emerged as interesting genomic targets in environmental atherogenesis since members of this family modify genetic programs in somatic cells through a "copy and paste" mechanism involving RNA intermediates, reverse transcriptase and endonuclease. To continue previous investigations, studies are proposed in this application to evaluate the expression of L1 during the course of atherosclerotic disease progression in the Apoetm1Unc mouse model, to evaluate the impact of vascular specific expression of L1 on atherosclerotic lesion occurrence and severity, and to elucidate molecular mechanisms of L1 activation in vSMCs and macrophages, two of the principal cell types in atherosclerosis. The central hypothesis to be tested is that progression of plaque formation is associated with L1 overexpression and genomic instability in cells within the atherosclerotic plaque. Further, it is hypothesized that L1 activation is mediated via epigenetic mechanisms that increase promoter activity and RNA polymerase II efficiency. These studies are the first to systematically examine the role of L1 and retrotransposition in diseases of the vascular wall. PUBLIC HEALTH RELEVANCE: Atherosclerosis continues to be responsible for most cases of cardiovascular mortality in the US. Recent studies have shown that the incidence of this disease is accelerated by environmental contaminants, but the genetic mechanisms that mediate this relationship are not fully understood. Studies are proposed in this application to study the role of virus-like sequences in the onset and progression of environmentally-induced atherosclerosis in experimental systems.

描述（由申请人提供）：动脉粥样硬化是工业化国家发病率和死亡率的主要原因，是一种与内皮损伤，炎症细胞募集（巨噬细胞和T细胞），血管平滑肌细胞（VSMC）的扩展以及内部凝聚力层的堆积相关的纤维增殖性疾病。临床疾病是由吞噬心脏，大脑或四肢的血管的阻塞引起的。动脉粥样硬化的早期阶段（动脉粥样硬化）涉及血管壁的炎症损伤，巨噬细胞的浸润和VSMC的不受控制的增殖。血管壁的氧化损伤是动脉粥样硬化反应的普通分母，血液胆固醇水平升高，高血压，糖尿病和吸烟被识别为主要危险因素。慢性暴露于与颗粒物相关的空气颗粒物和化学物质（例如多环芳烃）与啮齿动脉粥样硬化和灵长类动物的动脉粥样硬化的发育或加剧有关。相关性是苯并（a）pyrene（BAP）的生物学作用，一种以各种形式的污染形式存在的致癌物，并被细胞色素P450代谢，以损害DNA并引起氧化应激。 VSMC反复暴露于体内或体外会引起血管壁内动脉粥样硬化的变化。负责BAP动脉粥样硬化的分子机制涉及基因表达和DNA损伤的转录放松管制。感兴趣的是涉及人和鼠VSMC中C-HA-RAS基因激活以及长期散布的核元素（第1或L1）的反应。 L1已成为环境动脉动脉粥样硬化中有趣的基因组靶标，因为该家族的成员通过涉及RNA中间体，逆转录酶和内切清除酶的“复制和粘贴”机制修饰体细胞中的遗传程序。为了继续进行先前的研究，在此应用中提出了研究，以评估apoetm1unc小鼠模型中动脉粥样硬化疾病进展过程中L1的表达，以评估L1的血管性病变表达对动脉粥样硬化病变的出现和严重性的影响，并阐明L1在VSMC中的L1活化的分子机制，并在两种型号中的型号和MiCrophages in triply ocarmcass和mocrophages in triplage and carlcoplages。要测试的中心假设是，斑块形成的进展与动脉粥样硬化斑块内细胞中的L1过表达和基因组不稳定性有关。此外，假设L1激活是通过表观遗传机制介导的，从而提高启动子活性和RNA聚合酶II效率。这些研究是第一个系统地检查L1和逆转录位置在血管壁疾病中的作用的研究。公共卫生相关性：动脉粥样硬化继续负责美国大多数心血管死亡率。最近的研究表明，这种疾病的发生率是通过环境污染物加速的，但是介导这种关系的遗传机制尚未完全了解。在此应用中提出了研究，以研究病毒样序列在实验系统中环境诱导的动脉粥样硬化的发作和进展中的作用。