Novel Regulators of Vascular Disease

血管疾病的新型调节剂

• 批准号: 8598787
• 负责人: ANUPAM AGARWAL
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2016-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8598787
• 关键词: Ablation; Affect; Age-Months; Age-Years; Aging; Aging-Related Process; Animals; Arteries; Arteriosclerosis; Award; Bathing; Biology; Blood Vessels; Calcium; Cardiovascular system; Chronic Kidney Failure; Collagen; Core Facility; Data; Deposition; Descending aorta; Development; Disease; Down-Regulation; Elastin; Elastin Fiber; Elderly; Ferritin; Frequencies; Funding; Genetic; Goals; Growth Factor; Histology; Human; Image Analysis; Immunohistochemistry; Knockout Mice; Link; Medial; Medical center; Modification; Molecular; Morbidity - disease rate; Mus; Myography; NOS3 gene; Nephrology; Nitric Oxide; Organ; Osteoblasts; Outcome; Pathogenesis; Pathology; Patients; Peripheral Vascular Diseases; Phenotype; Physiologic pulse; Physiology; Population; Prevention; Process; Production; Proteins; Rattus; Relative (related person); Research; Research Infrastructure; Research Personnel; Research Training; Resistance; Resources; Rodent; Role; Series; Smooth Muscle; Smooth Muscle Myocytes; Sodium Chloride; Structure; System; Testing; Thick; Transforming Growth Factor beta; Transforming Growth Factors; Translating; Ultrasonography; United States National Institutes of Health; Up-Regulation; Vascular Diseases; Vascular calcification; Veterans; Work; age related; arterial stiffness; calcification; cerebrovascular; design; endothelial dysfunction; extracellular; feeding; heme oxygenase-1; human NOS3 protein; improved; indexing; interest; kidney vascular structure; molecular pathology; mortality; mouse model; new technology; novel; osteogenic; prevent; programs; protein expression; ranpirnase; research study; salt intake; systolic hypertension

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.

血管疾病的新调节剂 在20至90岁之间，动脉壁内膜媒体厚度增加， 促进动脉刚度。导管动脉刚度增加是 衰老相关疾病的发病机理，例如收缩压，脑血管， 心血管，肾血管和周围血管疾病 - 都代表着重要的 负担影响退伍军人人口。这个VA-PPA是带来的独特机会 四名VA研究人员一起研究导管动脉刚度的病理生物学。系列 在三个相互关联的项目和最先进的动物血管表型核心设施中 专注于与基质蛋白沉积相关的血管功能障碍的共同主题 和内侧钙化，已知在衰老期间增加动脉刚度的两个因素 慢性肾脏病（CKD）。 这三个项目和核心的特定对象是： 1。定义衰老过程减少内皮一氧化氮的机制（NO） 合成酶功能并改变转化生长因子-SS的血管产生（TGF-SS） 为了促进随着衰老而发展动脉刚度的发展（项目1：分子 老化的血管功能机制； PI：保罗·桑德斯）。工作 该项目的假设是主动TGF-SS与NO的比率是一个关键，可修改的比率 衰老的动脉刚度的决定因素。 2。确定Runx2在控制动脉僵硬和阐明分子中的作用 机制，使用一种新型的平滑肌特异性Runx2敲除鼠标模型（项目 2：动脉僵硬的分子机制； pi：yabing chen）。这 该项目的工作假设是，高盐的摄入量会引起表达 VSMC中的runx2，启动VSMC计算并促进伪像僵硬。 3。定义血红素加氧酶-1（HO-1）/铁蛋白系统在预防血管中的作用 通过下调Runx2和TGF-SS的钙化（（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/铁蛋白系统诱导的工作假设可防止血管 通过下调runx2和tgf-€的钙化。 4。支持最先进的核心设施（动物血管表型核心；导演： Edgar Jaimes）旨在提供动脉刚度的详细结构功能分析 和血管钙化。核心将由一个血管生理子组成 radiotelemetry，高频血管超声，微CT和内皮功能 （mysograph）;和一个分子病理学子核，用于组织学，免疫组织化学 和图像分析。核心将带给伯明翰VA医疗中心（BVAMC）新 研究血管生物学的技术。 这项研究工作的长期目标是为 将发现转化为改善衰老和CKD的心血管结局，并进一步建立 BVAMC的研究能力。