Novel Regulators of Vascular Disease

血管疾病的新型调节剂 在20至90岁之间，动脉壁内膜-中层厚度增加， 促进动脉硬化。增加的管道动脉僵硬度是 衰老相关疾病如收缩期高血压，脑血管， 心血管、肾血管和外周血管疾病-所有这些都代表了一个显著的 影响退伍军人的负担。这个VA-PPA是一个独特的机会， 四名退伍军人事务部研究人员一起研究管道动脉僵硬的病理生物学。一系列 三个相互关联的项目和最先进的动物血管表型核心设施将 关注与基质蛋白沉积相关的血管功能障碍的共同主题 和中膜钙化，这两个已知的因素会增加动脉硬化， 慢性肾病（CKD）。 这三个项目和核心项目的具体目标是： 1.定义衰老过程减少内皮一氧化氮（NO）的机制 合成酶功能和改变血管转化生长因子-β（TGF-β）的产生 以促进动脉硬化与年龄的发展（项目1：分子 衰老对血管功能的影响机制; PI：Paul Sanders）。工作 该项目的假设是活性TGF-β与NO的比例是一个关键的，可改变的 动脉硬化老化的决定因素。 2.确定Runx 2在调节动脉硬化中的作用，并阐明其分子机制。 机制，使用一种新的平滑肌特异性Runx 2基因敲除小鼠模型（项目 2：动脉硬化的分子机制; PI：Yabing Chen）。的 该项目的工作假设是，高盐摄入诱导表达 VSMC中的Runx 2，启动VSMC钙化并促进动脉硬化。 3.确定血红素氧合酶-1（HO-1）/铁蛋白系统在预防血管性心脏病中的作用。 通过下调Runx 2和TGF-β抑制钙化（项目3：HO-1/铁蛋白的作用 在老化期间的血管钙化中; PI：Anupam Agarwal）。实验将测试 HO-1/铁蛋白系统的诱导阻止血管生成的工作假设 钙化通过下调Runx 2和TGF-β。 4.支持最先进的核心机构（动物血管表型分析中心;负责人： 埃德加Jaimes）旨在提供动脉僵硬度的详细结构-功能分析 和血管钙化。核心将包括血管生理学子核心， 无线电遥测、高频血管超声、微型CT和内皮功能 （肌造影）;和一个分子病理学亚核心组织学，免疫组织化学 和图像分析。该核心将为伯明翰VA医疗中心（BVAMC）带来新的 研究血管生物学的技术。 这项研究工作的长期目标是奠定必要的基础， 将研究结果转化为改善衰老和CKD的心血管结局，并进一步建立 BVAMC的研究能力。

Novel Regulators of Vascular Disease Between 20 and 90 years of age, arterial wall intimal-media thickness increases, promoting arterial stiffness. Increased conduit artery stiffness is a key factor in the pathogenesis of aging-associated diseases such as systolic hypertension, cerebrovascular, cardiovascular, renovascular, and peripheral vascular diseases - all represent a significant burden affecting the Veteran population. This VA-PPA is a unique opportunity to bring together four VA investigators to study the pathobiology of conduit artery stiffness. A series of three inter-related projects and a state-of-the-art animal vascular phenotyping core facility will focus on the common theme of vascular dysfunction associated with matrix protein deposition and medial calcification, two factors known to increase arterial stiffness during aging and chronic kidney disease (CKD). The specific objectives of the three Projects and Core are to: 1. Define the mechanisms by which the aging process reduces endothelial nitric oxide (NO) synthase function and alters vascular production of Transforming Growth Factor-ss (TGF-ss) to facilitate the development of arterial stiffness with aging (Project 1: Molecular Mechanisms of Aging on Vascular Function; PI: Paul Sanders). The working hypothesis of this project is the ratio of active TGF-ss to NO is a critical, modifiable determinant of arterial stiffness of aging. 2. Determine the role of Runx2 in regulating arterial stiffening and elucidate the molecular mechanisms, using a novel smooth muscle-specific Runx2 knockout mouse model (Project 2: Molecular Mechanisms Underlying Arterial Stiffening; PI: Yabing Chen). The working hypothesis of this project is that a high salt intake induces the expression of Runx2 in VSMC, which initiates VSMC calcification and promotes arterial stiffening. 3. Define the role of the heme oxygenase-1 (HO-1)/ferritin system in the prevention of vascular calcification through downregulation of Runx2 and TGF-ss ((Project 3: Role of HO-1/Ferritin in Vascular Calcification During Aging; PI: Anupam Agarwal). Experiments will test the working hypothesis that induction of the HO-1/ferritin system prevents vascular calcification through downregulation of Runx2 and TGF-¿. 4. Support a state-of-the-art core facility (Animal Vascular Phenotyping Core; Director: Edgar Jaimes) designed to provide detailed structure-function analyses of arterial stiffness and vascular calcification. The core will consist of a vascular physiology subcore for radiotelemetry, high frequency vascular ultrasound, micro-CT and endothelial function (myography); and a molecular pathology subcore for histology, immunohistochemistry and image analysis. The core will bring to the Birmingham VA Medical Center (BVAMC) new technology to study vascular biology. The long-term goal of this research effort is to lay the essential groundwork necessary to translate the findings to improved cardiovascular outcomes in aging and CKD and further build the research capacity at the BVAMC.