Angiotensin (1-12) and Hypertension in the Elderly

项目摘要 高血压是一个主要的公共健康问题，随着人口老龄化，高血压的负担更加严重 人口。大量的实验数据表明，血管紧张素II(Ang II)是导致高血压的主要因素 高血压相关靶器官损害的发展。尽管数据表明经典的RAS 抑制剂发挥积极的治疗作用这些药物的长期影响的多中心研究 心血管发病率和死亡率显示出与其他类别的降压药相似的疗效 毒品。我们的假设是心脏和肾脏Ang-(1-12)是非肾素依赖型Ang的主要前体 II代，可能是压力相关靶器官损害进行性发展的原因。少校 本项目的目的是评估单抗和细胞穿透的治疗效果。 高效与改进相结合的纳米抗体(NBS)抗Ang-(1-12)人类序列 治疗依从性。正在进行的工作是针对人类Ang-(1-12)的C末端的单抗。 全动物血流动力学实验为血管紧张素转换酶体内中和能力的概念提供了证据。 (1-12)。研究将在人性化的高血压模型中进行，该模型通过植入人类 血管紧张素原(AGT)基因导入SD大鼠基因组。男性和女性的研究策略 转基因高血压大鼠将结合连续血压和心率记录进行评估 血浆Ang-(1-12)、Ang I、Ang II和Ang-(1-7)水平、血浆肾素活性和血清 醛固酮、心脏和肾功能变量。这些措施将在1周前、1周和4周采取 在开始使用Ang-(1-12)单抗或纳米抗体(NB)治疗后。这样做的有效性 控制血压的免疫疗法将在给予抗体的实验中进一步量化。 转基因高血压大鼠联合赖诺普利或valsartan。建议的高度创新研究 将为涉及中和Ang-(1-12)的新型高血压治疗策略提供概念基础。

Project Summary The burden of high blood pressure, a major public health problem, is aggravated by an aging human population. A plethora of experimental data points to angiotensin II (Ang II), as the major contributing factor in the development of hypertension-related target organ damage. Although data suggested that classic RAS inhibitors exert positive therapeutic benefits multi-center studies of the long-term effects of these drugs on cardiovascular morbidity and mortality showed an effectiveness similar to other classes of antihypertensive drugs. Our hypothesis is that cardiac and renal Ang-(1-12), as a primary precursor for non-renin dependent Ang II generation, may account for the progressive development of pressure-related target organ damage. The major goal of this project is to evaluate the therapeutic effects of monoclonal antibodies (mABs) and cell penetrating nanobodies (Nbs) against the human sequence of Ang-(1-12) through combining high efficacy with improve treatment adherence. Work in progress characterized mAbs against the C-terminus of human Ang-(1-12). Whole animal hemodynamic experiments provide proof of concept on the ability of in vivo neutralization of Ang- (1-12). Research will be performed in a humanized model of hypertension engineered by insertion of the human angiotensinogen (AGT) gene into the genome of Sprague Dawley rats. Research strategies in male and female transgenic hypertensive rats will combine continuous blood pressure and heart rate recordings with assessment of plasma levels of Ang-(1-12), Ang I, Ang II, and Ang-(1-7), measurements of plasma renin activity, and serum aldosterone, and cardiac and renal function variables. These measures to be taken before and at 1 and 4 weeks after initiation of therapy with either Ang-(1-12) mAbs or nanobodies (NB). The effectiveness of this immunotherapy in blood pressure control will be further quantified in experiments in which antibodies are given to transgenic hypertensive rats in combination with lisinopril or valsartan. The proposed highly innovativestudies will provide a conceptual basis for novel hypertension treatment strategies involving neutralization of Ang-(1-12).