Novel Regulators of Vascular Disease

血管疾病的新调节剂 在20到90岁之间，动脉壁内膜-中层厚度增加， 促进动脉僵硬。导管动脉僵硬的增加是导致 与衰老相关的疾病的发病机制，如收缩期高血压、脑血管、 心血管、肾血管和外周血管疾病--所有这些都代表着显著的 影响退伍军人的负担。这次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导管动脉僵硬的病理生物学。一系列 三个相互关联的项目和一个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 和中层钙化，这两个已知的因素会在衰老和 慢性肾病(CKD)。 三个项目和核心的具体目标是： 1.确定衰老过程降低内皮一氧化氮(NO)的机制 合酶功能与转化生长因子-ss(TGF-ss)的血管生成 促进随年龄增长的动脉僵硬(项目1：分子 衰老对血管功能的作用机制(PI：Paul Sanders)在工作中 本项目的假设是，活性的转化生长因子-SS与一氧化氮的比率是一个关键的、可修改的 老年动脉僵硬的决定因素。 2.确定Runx2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Runx2基因敲除小鼠模型(项目 2：动脉硬化的分子机制；PI：陈亚兵)。这个 该项目的工作假设是，高盐摄入量会诱导 VSMC中的Runx2，它启动VSMC的钙化并促进动脉硬化。 3.明确血红素加氧酶-1(HO-1)/铁蛋白系统在预防血管病变中的作用 下调Runx2和TGF-ss的钙化作用(项目3：HO-1/铁蛋白的作用 在衰老过程中的血管钙化；PI：Anupam Agarwal)。实验将测试 HO-1/铁蛋白系统的诱导防止血管形成的工作假说 通过下调Runx2和转化生长因子-β的表达而发生钙化。 4.支持最先进的核心设施(动物血管表型核心；主任： Edgar Jaimes)设计来提供动脉僵硬的详细结构-功能分析 和血管钙化。核心将由血管生理学分核心组成，用于 放射遥测、高频血管超声、微型CT与血管内皮功能 (肌造影术)；以及组织学的分子病理学亚核心，免疫组织化学 和图像分析。核心将为伯明翰退伍军人医疗中心(BVAMC)带来新的 研究血管生物学的技术。 这项研究的长期目标是为以下工作奠定必要的基础 将这些发现转化为老龄化和慢性肾脏病心血管结果的改善，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.