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Principal Investigator: Yagna Jarajapu
Organization: NORTH DAKOTA STATE UNIVERSITY
Fiscal Year: 2021
Award: $253,750
Funding agency: National Institute on Aging
Targeting Mas Receptor for Diabetic Vascular Disease in Older Adults
Abstract
Prevalence of diabetes is high among older adults and is expected to rise, and diabetes increases risk for
cardiovascular disease. Accumulated evidence suggests that bone marrow-derived progenitor cells maintain
vascular health and promote rapid repair following vascular injury. This innate vascular protection is
diminished with aging and diabetes due to impaired mobilization of EPCs from bone marrow into circulation
and decreased ability to repair damaged blood vessels. Therefore approaches that preserve EPC mobilization
and function will prevent the development of vascular disease in older adults with diabetes. We hypothesize
that the Mas receptor, the functional mediator of the vasoprotective axis of renin angiotensin system, confers
mobilization and reparative functions in EPCs and that early intervention with MasR activation would
preserve innate vasoprotection and prevents the development of vascular disease with aging and diabetes.
This hypothesis is based on our novel findings that showed angiotensin converting enzyme-2 that generates
heptapeptide angiotensin (Ang)-(1-7), the endogenous activator of MasR, is down-regulated with aging and
diabetes. Importantly, genetic deficiency of MasR (MasR-KO) precipitates EPC moblilopathy and
vasoreparative dysfunction following ischemic vascular injury, similar to aging and diabetes. Three aims are
proposed to test the hypothesis. Aim-1 will define the role of MasR in the mobilization and vasoreparative
functions of EPCs by using radiation chimeras of MasR-KO mice. Aim-2 will test the beneficial effects of long-
term activation of MasR on the development of vasoreparative dysfunction with aging and diabetes. This will
be accomplished by overexpressing Ang-(1-7) by adenoviral or nonviral approaches. We will test if the
overexpression of Ang-(1-7) will reverse the vasoreparative dysfunction in CD34+EPCs derived from older
adults with diabetes. Therefore Aim-2 will provide the proof-of-concept for the translational potential of the
study. Aim 3 will demonstrate the involvement of novel pathways that mediate the reversal of mobilization
and vasoreparative dysfunctions in diabetic EPCs by MasR activation, Slit/Robo/ROCK pathway and
TERT/mitoROS/NO pathway, respectively. Overall, this study will provide a novel mechanism-based
pharmacological approach for reversal as well as prevention of diabetic vascular disease in older adults with
diabetes.
Terms: <ACE2><Age><Aging><Ang I (1-7)><Approaches to prevention><Blood Circulation><Blood Vessels><Bloodstream><Bone Marrow><Bone Marrow Reticuloendothelial System><CD34><CD34 gene><Chimera><Chimera organism><Circulation><Clinical><Clinical Evaluation><Clinical Testing><Clinical Trials><Cor pulmonale><Development><Diabetes Mellitus><Diabetic Angiopathies><Diabetic Vascular Complications><Diabetic Vascular Diseases><Diabetic Vascular Disorder><Diabetic mouse><Dysfunction><Early Intervention><Elderly><Functional disorder><Genetic><HPCA1><Health><Hyperglycemia><Impairment><Individual><Intervention><Intervention Strategies><KO mice><Knock-out Mice><Knockout Mice><Ligands><Long-Term Effects><Longterm Effects><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Messenger RNA><Mice><Mice Mammals><Morbidity><Morbidity - disease rate><Murine><Mus><Natural regeneration><Null Mouse><Outcome><Pathway interactions><Pharmacology><Physiopathology><Prevalence><Prevention><Prevention approach><Progenitor Cells><Pulmonary Heart Disease><Pulmonary Heart Disorder><Radiation Chimera><Receptor Activation><Receptor Protein><Regeneration><Renin-Angiotensin System><Risk><Role><Telomerase><Testing><Vascular Diseases><Vascular Disorder><advanced age><ages><angiotensin I (1-7)><angiotensin converting enzyme 2><angiotensin converting enzyme II><angiotensin-(1-7)><base><blood damage><blood vessel disorder><cardiopulmonary disease><cardiopulmonary disorder><cardiovascular disease risk><cardiovascular disorder risk><clinical test><developmental><diabetes><diabetes mouse model><diabetic><elders><endothelial progenitor cell><endothelial stem cell><geriatric><hyperglycemic><improved><injury to the vasculature><interventional strategy><ischemia injury><ischemic injury><late life><later life><mRNA><microvascular complications of diabetes><mortality><novel><older adult><older person><overexpress><overexpression><paracrine><pathophysiology><pathway><preservation><prevent><preventing><progenitor cell function><receptor><receptor expression><regenerate><repair><repair function><repaired><reparative ability><reparative capacity><reparative function><reparative potential><research clinical testing><senior citizen><sex><social role><stem cell function><stem cells><therapeutic target><vascular><vascular dysfunction><vascular injury><vasculopathy>