Mechanisms of augmented atherosclerotic progression with aging

随着衰老加剧动脉粥样硬化进展的机制

基本信息

批准号：
9351469
负责人：
Lisa A Lesniewski
金额：
$ 31.03万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-15 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9351469
关键词：
Adult Age Aging Aorta Apolipoprotein E Arterial Fatty Streak Arteries Atherosclerosis Binding Biological Assay Blood Vessels Blood flow Cardiovascular Diseases Caring Carotid Arteries Cause of Death Cell Culture System Cell physiology Cells Comorbidity Consumption Development Diet Disease Disease Progression Elderly Endothelial Cells Endothelium Epidemic Experimental Genetics Exposure to Fatty acid glycerol esters Fibrosis Functional disorder Future Gene Proteins Gene Targeting Genetic Models Growth High Fat Diet Impairment In Vitro Inflammation Ischemia Knockout Mice Lesion Ligation Limb structure Measures Mediating Messenger RNA MicroRNAs Modeling Morbidity - disease rate Mus Mutation Obesity Oxidative Stress Pharmacology Physiological Proteomics Regulation Reverse Transcriptase Polymerase Chain Reaction Risk Role Signal Pathway Small Interfering RNA Surgical Models TP53 gene Transcriptional Regulation Translations Untranslated RNA Vascular Diseases Western Blotting aged angiogenesis arterial stiffness c-myc Genes cardiovascular disorder prevention differential expression disorder risk factor C feeding in vivo inhibitor/antagonist insight interest member mortality mouse model new therapeutic target novel overexpression protein expression public health relevance screening shear stress tissue culture transcription factor transcriptome sequencing

项目摘要

DESCRIPTION (provided by applicant): Advancing age is the primary non-modifiable risk factor for cardiovascular diseases (CVD), such as atherosclerosis, and arterial dysfunction is an important contributor to this increased disease risk. The proposed studies will explore the novel hypothesis that an age-associated reduction in microRNA, miR-92a and its cluster miR-17-92, underlie age-associated arterial dysfunction and accelerated atherosclerotic disease progression. Because obesity is epidemic in US adults and is often a co-morbidity of older age, we will study both normal chow and high fat fed young and old mice to determine if aging per se exaggerates the negative influence of diet-induced obesity on vascular function and disease and if this is mediated by further decreases in arterial miR-92. We will utilize the well-established B6D2F1 mouse model of vascular aging and manipulate miR-92 by in vivo treatment with inhibitor and mimic oligomers as well as utilize genetic models to both up - and down-regulate miR-17-92, in the endothelium and whole body; respectively. We will assess measures of arterial function, such as endothelium dependent dilation, angiogenesis and large artery stiffening as well as assess atherosclerotic disease progression using a surgical model of disturbed carotid artery blood flow in mice crossed into an athero-prone background. Using targeted and unbiased approaches, we will explore the downstream targets of miR-92a/miR-17-92 and how these impact arterial function and disease. Last, using in vitro cell and tissue culture models we will determine upstream modulators of miR-17-92 expression, including regulation by the transcription factors c-myc and p53, as well as the role of altered shear stress in the regulation of miR-17-92 expression. The results will elucidate a novel mechanism underlying age-associated vascular dysfunction and disease risk and will provide critical evidence for a novel therapeutic target that may be effective in the treatment of CVD in older adults.

描述（由适用提供）：前进的年龄是心血管疾病（CVD）的主要不可抑制的危险因素，例如动脉粥样硬化和动脉功能障碍，是这种增加的疾病风险的重要促进者。拟议的研究将探索新的假设，即MicroRNA，miR-92a及其群集miR-17-92，与年龄相关的动脉功能障碍和加速动脉粥样硬化疾病进展相关的降低。由于肥胖症在美国成年人中是流行病的，并且通常是老年人的同胞，因此我们将研究正常的和高脂肪喂养的小鼠和老年小鼠，以确定衰老本质上是否夸大了饮食诱导的肥胖对血管功能和疾病的负面影响，并且在动脉miR-92中进一步下降的饮食介导了饮食诱导的肥胖症。用抑制剂和模仿低聚物的体内处理，并利用遗传模型在内皮和整个身体中向上和下调miR-17-92；分别。我们将评估动脉功能的度量，例如依赖内皮的词典，血管生成和大动脉僵硬，以及评估动脉粥样硬化疾病进展，使用障碍的颈动脉血流的手术模型交叉进入动脉粥样硬化背景。使用靶向和公正的方法，我们将探索miR-92A/miR-17-92的下游靶标，以及这些如何影响动脉功能和疾病。最后，使用体外细胞和组织培养我们将确定miR-17-92表达的上游调节剂，包括转录因子C-Myc和p53的调节，以及剪切应力改变在MIR-17-92表达调节中的作用。该结果将阐明一种与年龄相关的血管功能障碍和疾病风险的新型机制，并将为新型治疗靶标提供重要的证据，该靶标可能有效治疗老年人的CVD。