Angiotensin (1-12) and Hypertension in the Elderly

血管紧张素 (1-12) 与老年人高血压

基本信息

批准号：
10370035
负责人：
CARLOS M FERRARIO
金额：
$ 23.25万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10370035
关键词：
ACE2 Adherence Adult Affinity Age Aging Aldosterone Amino Acid Sequence Angiotensin II Angiotensin II Receptor Angiotensin-Converting Enzyme Inhibitors Angiotensinogen Angiotensins Animal Experimentation Animals Antibodies Antibody Therapy Antihypertensive Agents Atrial Fibrillation Attenuated Blood Blood Pressure Cardiac Cardiac Myocytes Cardiovascular Physiology Cardiovascular system Cells Cessation of life Chymase Clinical Data Dementia Development Effectiveness Elderly Engineering Essential Hypertension Event Exclusion FDA approved Female Functional disorder Generations Genes Genome Goals Grant Heart Heart Diseases Heart Rate Heart failure Hematologic Neoplasms High Prevalence Hormones Human Hypertension Hypertrophy Immunosuppression Immunotherapy Inbred WKY Rats Individual Infusion procedures Injections Kidney Left Left Ventricular Dysfunction Left ventricular structure Life Lipids Lisinopril Liver Long-Term Effects Malignant Neoplasms Measurement Measures Modeling Monoclonal Antibodies Morbidity - disease rate Multicenter Studies Myocardial Infarction Newly Diagnosed Oral Organ Pathogenesis Pathologic Pathway interactions Patients Peptidyl-Dipeptidase A Pharmaceutical Preparations Plasma Population Prevention strategy Public Health Rattus Renal function Renin Renin-Angiotensin System Research Residual state Risk Risk Reduction Role Serum Site Solid Neoplasm Sprague-Dawley Rats Therapeutic Therapeutic Effect Time Tissues Transgenic Organisms Vascular remodeling Ventricular Dysfunction Work aged auricular appendage base blood pressure regulation cancer therapy cardiovascular risk factor effective therapy efficacy evaluation experimental study heart function hemodynamics human old age (65+)hypertension treatment improved in vivo inhibitor/antagonist innovation male medication compliance mild cognitive impairment mortality nanobodies novel patient population polyclonal antibody pressure tissue processing treatment adherence treatment strategy urinary valsartan

项目摘要

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).

项目概要人类老龄化加剧了高血压这一重大公共卫生问题的负担人口。大量实验数据表明血管紧张素 II (Ang II) 是导致血管紧张素转换酶升高的主要因素。高血压相关靶器官损害的发展。尽管数据表明经典 RAS 抑制剂发挥积极的治疗效果对这些药物的长期影响进行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抗高血压药物相似的有效性药物。我们的假设是心脏和肾脏 Ang-(1-12) 作为非肾素依赖性 Ang 的主要前体第二代，可能解释了与压力相关的靶器官损伤的逐渐发展。主要该项目的目标是评估单克隆抗体（mAB）和细胞穿透的治疗效果纳米抗体（Nbs）针对人类Ang-（1-12）序列，通过结合高效与改善治疗依从性。正在进行的工作描述了针对人 Ang-(1-12) C 末端的 mAb 的特征。整个动物血流动力学实验提供了体内中和 Ang- 能力的概念证明。（1-12）。研究将在通过插入人类基因设计的人性化高血压模型中进行血管紧张素原（AGT）基因进入斯普拉格道利大鼠的基因组。男性和女性的研究策略转基因高血压大鼠将连续血压和心率记录与评估相结合 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的测量醛固酮以及心脏和肾功能变量。这些措施应在产前 1 周和 4 周时采取开始使用 Ang-(1-12) mAb 或纳米抗体 (NB) 治疗后。此方法的有效性免疫疗法在血压控制中的作用将在给予抗体的实验中进一步量化与赖诺普利或缬沙坦联合治疗转基因高血压大鼠。拟议的高度创新的研究将为涉及中和Ang-(1-12)的新型高血压治疗策略提供概念基础。