Mechanisms of augmented atherosclerotic progression with aging

 描述（由申请人提供）：年龄增长是心血管疾病（CVD）（如动脉粥样硬化）的主要不可改变的风险因素，动脉功能障碍是这种疾病风险增加的重要因素。拟议的研究将探索新的假设，即年龄相关的microRNA，miR-92 a及其簇miR-17-92的减少是年龄相关的动脉功能障碍和加速动脉粥样硬化疾病进展的基础。由于肥胖在美国成年人中流行，并且通常是老年人的共病，我们将研究正常食物和高脂肪喂养的年轻和老年小鼠，以确定衰老本身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，以及这是否由动脉miR-92的进一步减少介导。我们将利用成熟的血管老化B6 D2 F1小鼠模型，通过抑制剂和模拟寡聚体体内处理来操纵miR-92，并利用遗传模型分别在内皮和全身上调和下调miR-17-92。我们将评估动脉功能的措施，如内皮依赖性扩张，血管生成和大动脉硬化，以及评估动脉粥样硬化疾病的进展，使用一个手术模型的干扰颈动脉血流在小鼠交叉到一个动脉粥样硬化倾向的背景。使用靶向和无偏倚的方法，我们将探索miR-92 a/miR-17-92的下游靶点以及这些靶点如何影响动脉功能和疾病。最后，利用体外细胞和组织培养 模型，我们将确定上游调控miR-17-92的表达，包括调控的转录因子c-myc和p53，以及改变剪切应力的作用，在miR-17-92的表达调控。这些结果将阐明与年龄相关的血管功能障碍和疾病风险的新机制，并将为可能有效治疗老年人CVD的新治疗靶点提供关键证据。

 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.