Blood Pressure -- Determinants & Controllers

描述(由申请人提供)： 自1982年PPG成立以来，该计划的总体目标一直是了解动脉压的长期调节和高血压的后果。目前赠款的统一假设集中在这样的概念上，即肾脏控制长期的动脉压水平，当遗传易感性的盐摄入可以重要地影响肾脏功能和全身血管系统的结构和功能时。项目1将利用Dahl盐敏感大鼠(SS)来研究高盐饮食如何刺激肾髓质粗升支(MTAL)中活性氧物种(ROS)的过量产生，从而导致流向肾髓质的血流量减少、钠排泄减少和高血压。项目2假设，在盐源性高血压的早期阶段，炎症过程是由渗透的巨噬细胞启动的，巨噬细胞产生血管紧张素II(AngII)，刺激ROS的产生，从而增加高血压和肾脏损伤的严重程度。项目3将寻找细胞色素P4504A基因之一(CYP4A)的突变，这是SS大鼠潜在的遗传缺陷，在压力性心房利尿受损和高血压的发展中起着重要的原因作用。项目4研究了血管紧张素Ⅱ在维持正常血管反应性中的许可作用，以及SS肾素等位基因缺陷如何导致氧化应激增加和血管松弛受损。项目5着重于高血压时的微循环和控制和改变器官和组织血流的机制，以及在SS大鼠中发现的血管紧张素Ⅱ刺激的O2减少抑制血管内皮生长因子信号通路导致微血管稀疏和血管生成抑制的影响。这些项目中的每一个都利用了独特的遗传大鼠品系(共生、同源和转基因)，这些品系提供了感兴趣的特征和一个基因定义的对照品系。高血压影响着5000多万美国人，在北美75%的患者中仍处于基本失控状态，导致中风、心脏病和肾脏疾病的发病率增加，从而导致医疗成本不断上升。该计划反映了长期在协同环境中分享想法的经验，旨在促进我们对高血压的理解，并为可能更好地控制这种疾病的药物设计确定新的靶点。

DESCRIPTION (provided by applicant): Since the inception of this PPG in 1982, the overall goal of this program has been to achieve an understanding of the long-term regulation of arterial pressure and the consequences of high blood pressure. The unifying hypothesis of the present grant centers on the concept that the kidney controls the long-term level of arterial pressure and when genetically predisposed salt intake can importantly influence kidney function and the structure and function of the systemic vasculature. Project 1 will utilize Dahl salt-sensitive rats (SS) to study how a high salt diet may stimulate excess production of reactive oxygen species (ROS) in the renal medullary thick ascending limb (mTAL) leading to reduction of blood flow to the renal medulla, reduction in sodium excretion and hypertension. Project 2 hypothesizes that during the early phase of saltinduced hypertension an inflammatory process is initiated by infiltrating macrophages that produces angiotensin II (ANGII) that stimulates the production of ROS thereby increasing the severity of hypertension and renal injury. Project 3 will search for a mutation in one of the cytochrome P4504A genes (CYP4A) that is the underlying genetic defect in the SS rat that plays an important causal role in the impaired pressurenatriuresis and the development of hypertension. Project 4 examines the permissive role that ANGII plays in maintaining normal vascular reactivity and how defects in the SS renin allele lead to increased oxidative stress and impaired vascular relaxation. Project 5 focuses on the microcirculation and the mechanisms that control and alter organ and tissue perfusion in hypertension and the impact that reductions in ANGllstimulated O2 inhibit the VEGF signaling pathway leading to microvessel rarefaction and inhibition of angiogenesis that is found in the SS rat. Each of these projects utilize unique genetic rat strains (consomic, congenic, and transgenic) that provide the trait of interest and a genetically defined control strain. Hypertension affects more than 50 million Americans and remains largely uncontrolled in 75% of patients in North America leading to an increased incidence of stroke, heart, and renal disease, that contribute to escalating health care costs. The program reflects a long-standing experience of shared ideas in a synergistic environment aimed toward advancing our understanding of hypertension and the identification of novel targets for drug design that may better control this disease.