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Principal Investigator: CARLOS M FERRARIO
Organization: WAKE FOREST UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2021
Award: $232,500
Funding agency: National Institute on Aging
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).
Terms: <21+ years old><65+ years old><ACE Inhibitors><ACE2><Adherence><Adult><Adult Human><Affinity><Age><Aged 65 and Over><Aging><Aldosterone><Amentia><Amino Acid Sequence><AngII><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin I-Converting Enzyme Inhibitors><Angiotensin II><Angiotensin II Receptor><Angiotensin-Converting Enzyme Antagonists><Angiotensin-Converting Enzyme Inhibitors><Angiotensin-Forming Enzyme><Angiotensinogen><Angiotensinogenase><Angiotensins><Animal Experimental Use><Animal Experimentation><Animal Research><Animals><Anti-Hypertensive Agents><Anti-Hypertensive Drugs><Anti-Hypertensives><Antibodies><Antibody Therapy><Antihypertensive Agents><Antihypertensive Drugs><Antihypertensives><Atrial Appendage><Atrial Fibrillation><Atrium Appendage><Attenuated><Auricular Fibrillation><BP control><BP homeostasis><BP management><BP regulation><Blood><Blood Plasma><Blood Pressure><Blood Reticuloendothelial System><Blood Serum><Body Tissues><CD143 Antigens><Cancer Treatment><Cancers><Carboxycathepsin><Cardiac><Cardiac Chronotropism><Cardiac Diseases><Cardiac Disorders><Cardiac Muscle Cells><Cardiac Myocytes><Cardiac infarction><Cardiocyte><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular Physiology><Cardiovascular system><Cell Body><Cells><Cessation of life><Chymase><Clinical><Clinical Treatment Moab><Common Rat Strains><Data><Death><Dementia><Development><Dipeptidyl Peptidase A><Drugs><Dysfunction><Effectiveness><Elderly><Endocrine Gland Secretion><Engineering><Essential Hypertension><Event><Exclusion><FDA approved><Female><Functional disorder><Generations><Genes><Genome><Goals><Grant><Heart><Heart Atrium Appendage><Heart Diseases><Heart Muscle Cells><Heart Rate><Heart Vascular><Heart failure><Heart myocyte><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><High Prevalence><Hormones><Human><Hypertensinogen><Hypertension><Hypertrophy><Hypotensive Agent><Hypotensive Drugs><Hypotensives><Immune mediated therapy><Immunologically Directed Therapy><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><Inbred WKY Rats><Individual><Infusion><Infusion procedures><Injections><Kidney><Kidney Urinary System><Kininase A><Kininase II><Kininase II Antagonists><Kininase II Inhibitors><Left><Left Ventricles><Left Ventricular Dysfunction><Left ventricular structure><Life><Lipids><Lisinopril><Liver><Long-Term Effects><Longterm Effects><MMCP-1><Malignant Hematologic Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Measurement><Measures><Medication><Modeling><Modern Man><Monoclonal Antibodies><Morbidity><Morbidity - disease rate><Multi-center studies><Multicenter Studies><Myocardial Infarct><Myocardial Infarction><Newly Diagnosed><Oral><Organ><Pathogenesis><Pathologic><Pathway interactions><Patients><Peptidyl-Dipeptidase A><Pharmaceutic Preparations><Pharmaceutical Preparations><Physiopathology><Plasma><Plasma Serum><Population><Preventative strategy><Prevention strategy><Preventive strategy><Primary Protein Structure><Prinivil><Proangiotensin><Public Health><Rat><Rats Mammals><Rattus><Renal function><Renin><Renin-Angiotensin System><Renin-Substrate><Research><Residual><Residual state><Reticuloendothelial System, Serum, Plasma><Risk><Risk Reduction><Role><Serum><Site><Solid Neoplasm><Solid Tumor><Sprague-Dawley Rats><Therapeutic><Therapeutic Effect><Therapeutic Hormone><Time><Tissues><Transgenic Organisms><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vascular remodeling><Ventricular Dysfunction><WKY Rats><Wistar Kyoto Rats><Work><Zestril><adulthood><advanced age><age 65 and greater><age 65 and older><aged><aged 65 and greater><aged ≥65><ages><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-cancer therapy><antibody based therapies><antibody treatment><antibody-based therapeutics><antibody-based treatment><anticancer therapy><auricular appendage><base><blood pressure control><blood pressure homeostasis><blood pressure management><blood pressure regulation><cancer therapy><cancer-directed therapy><cardiac failure><cardiac function><cardiac infarct><cardiomyocyte><cardiovascular function><cardiovascular risk><cardiovascular risk factor><chymase-1><chymotrypsin-like protease><circulatory system><coronary attack><coronary infarct><coronary infarction><developmental><drug adherence><drug compliance><drug/agent><effective therapy><effective treatment><efficacy analysis><efficacy assessment><efficacy evaluation><efficacy examination><elders><evaluate efficacy><examine efficacy><experiment><experimental research><experimental study><function of the heart><geriatric><heart attack><heart auricle><heart disorder><heart function><heart infarct><heart infarction><hemodynamics><hepatic body system><hepatic organ system><high blood pressure><human old age (65+)><hyperpiesia><hyperpiesis><hypertension treatment><hypertensive disease><idiopathic hypertension><immune suppression><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><in vivo><inhibitor><inhibitor/antagonist><innovate><innovation><innovative><kidney function><late life><later life><mAbs><male><malignancy><mast cell protease><mast cell protease 1><mast cell protease I><mast cell proteinase-1><medication adherence><medication compliance><mild cognitive disorder><mild cognitive impairment><mortality><nanobodies><nanobody><neoplasm/cancer><novel><old age><older adult><older person><pathophysiology><pathway><patient population><polyclonal antibody><pressure><primary hypertension><protein sequence><regulate BP><regulate blood pressure><renal><sdAb><senior citizen><single domain antibodies><skeletal muscle protease><social role><tissue processing><transgenic><treatment adherence><treatment strategy><urinary><valsartan>