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

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

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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).

项目摘要高血压的负担是一个重大的公共卫生问题，受到人类老龄化的加剧人口。大量的实验数据指向血管紧张素II（ANG II），是主要促成因素与高血压相关的靶器官损伤的发展。尽管数据表明经典RA 抑制剂对这些药物对这些药物的长期影响的阳性治疗益处多中心研究心血管发病率和死亡率显示出类似于其他类别的降压的有效性毒品。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 II产生，可以解释与压力相关的目标器官损害的逐步发展。专业该项目的目标是评估单克隆抗体（mAb）和细胞穿透的治疗作用通过将高疗效与改善相结合的人类（1-12）的人类序列，纳米型（NB）（NBS）治疗依从性。正在进行的工作表征对人类人体的C末端的MAB（1-12）。整个动物血流动力学实验提供了有关体内中和符合能力的概念证明（1-12）。研究将在人类的高血压模型中进行。血管紧张素原（AGT）基因进入Sprague Dawley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血浆（1-12），Ang I，Ang II和Ang-（1-7）的血浆水平，血浆肾素活性的测量和血清醛固酮以及心脏和肾功能变量。这些措施要在1和4周之前和4周在使用Ang-（1-12）mAb或纳米型（NB）进行治疗后。这个有效性在给予抗体的实验中，将进一步量化血压控制中的免疫疗法将转基因高血压大鼠与赖诺普利或瓦尔萨坦结合使用。拟议的高度创新性将为涉及Ang-中和（1-12）的新型高血压治疗策略提供概念基础。