Angiotensin (1-12) and Hypertension in the Elderly

项目摘要 高血压是一个主要的公共卫生问题，其负担因人类老龄化而加重 人口大量的实验数据表明血管紧张素II（Ang II）是血管紧张素受体（VEGF）表达的主要影响因素。 高血压相关靶器官损害的发展。虽然数据表明，传统的RAS 抑制剂发挥积极的治疗效益的多中心研究，这些药物的长期影响， 心血管发病率和死亡率显示出与其他类别的抗高血压药物相似的有效性。 毒品我们的假设是心脏和肾脏的Ang-（1-12）作为非肾素依赖性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。主要 本项目的目的是评估单克隆抗体（mAB）和细胞穿透的治疗效果， 针对人Ang-（1-12）序列的纳米抗体（Nbs）通过将高效与改善相结合， 治疗依从性。正在进行的工作表征了针对人Ang-（1-12）的C-末端的mAb。 全动物血液动力学实验提供了体内中和Ang-2的能力的概念证明。 （1-12）。研究将在通过插入人类高血压基因工程的人源化高血压模型中进行。 血管紧张素原（AGT）基因导入Sprague道利大鼠基因组。男性和女性的研究策略 转基因高血压大鼠将结合联合收割机连续血压和心率记录与评估 Ang-（1-12）、Ang I、Ang II和Ang-（1-7）的血浆水平，血浆肾素活性和血清 醛固酮和心肾功能变量。这些措施应在第1周和第4周之前采取 在用Ang-（1-12）mAb或纳米抗体（NB）开始治疗后。的有效性 将在给予抗体的实验中进一步量化血压控制中的免疫疗法 转基因高血压大鼠与赖诺普利或缬沙坦联合给药。提出的高度创新的研究 将为涉及Ang-（1-12）中和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).