Blood Pressure -- Determinants & Controllers

描述（由申请人提供）： 自1982年PPG成立以来，该计划的总体目标是了解动脉压的长期调节和高血压的后果。本资助的统一假设集中在肾脏控制动脉压的长期水平的概念上，并且当遗传倾向的盐摄入量可以重要地影响肾功能以及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）研究高盐饮食如何刺激肾髓质粗升支（mTAL）中活性氧（ROS）的过量产生，导致肾髓质血流量减少，钠排泄减少和高血压。项目2假设，在盐诱导的高血压的早期阶段，炎症过程是由浸润的巨噬细胞启动的，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损伤的严重程度。项目3将寻找细胞色素P4504A基因（CYP4A）中的一个突变，该突变是SS大鼠中的潜在遗传缺陷，在压力性尿失禁受损和高血压的发展中起着重要的因果作用。项目4研究了ANGII在维持正常血管反应性中的容许作用，以及SS肾素等位基因的缺陷如何导致氧化应激增加和血管舒张受损。项目5集中于微循环和控制和改变高血压中器官和组织灌注的机制，以及ANGl刺激的O2的减少抑制VEGF信号通路导致微血管稀疏和抑制SS大鼠中发现的血管生成的影响。这些项目中的每一个都利用了独特的遗传大鼠品系（同源、同源和转基因），这些品系提供了感兴趣的性状和遗传上确定的对照品系。高血压影响超过5000万美国人，并且在北美75%的患者中基本上不受控制，导致中风、心脏病和肾病的发病率增加，这导致医疗保健成本不断上升。该计划反映了在协同环境中共享想法的长期经验，旨在促进我们对高血压的理解，并确定可以更好地控制这种疾病的药物设计的新靶点。

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.