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Principal Investigator: Yagna Jarajapu
Organization: NORTH DAKOTA STATE UNIVERSITY
Fiscal Year: 2019
Award: $50,000
Funding agency: National Institute on Aging
Healthy cerebral vasculature and adequate blood flow determine overall brain health. Vascular cognitive
impairment and dementia (VCID) has now been recognized as a clinical condition with cerebrovascular
dysfunction as the underlying pathological mechanism. Aging and diabetes are independent risk factors for
vascular disease, and the prevalence of diabetes is higher among older adults and is expected to rise.
Accumulated evidence suggests that bone marrow-derived hematopoietic stem/progenitor cells (HSPCs)
maintain vascular health and promote re-endothelialization and revascularization following vascular damage.
This innate vascular protection is diminished with aging and diabetes due to impaired mobilization of HSPCs
from bone marrow into circulation and decreased ability to repair damaged blood vessels. Therefore
approaches that preserve HSPC mobilization and function will prevent the development of VCID in older
adults with diabetes. We hypothesize that the vasoprotective axis of renin angiotensin system, confers
mobilization and reparative functions in HSPCs, and that early interventions that activate this pathway 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 Mas receptor (MasR), is down-regulated
with aging and diabetes in CD34+ HSPCs. Importantly, genetic deficiency of MasR (MasR-KO) precipitated
HSPC mobilopathy and vasoreparative dysfunction following ischemic vascular injury, similar to aging and
diabetes. Pharmacological treatment with Ang-(1-7) reversed HSPC mobilopathy and restored ischemic
vascular repair in diabetic mice. The long-term goal of this proposal is to provide proof-of-concept for the
potential of ACE2 or MasR activation or cell-based therapies that involve overexpression of ACE2 or Ang-(1-7)
in the treatment of VCID. The investigator has expertise in all of the technologies needed to accomplish the
objective except experimental evaluation of cognitive functions in aging mice with diabetes. The first step
towards meeting with the objective is to acquire and install the necessary equipment for cognitive evaluation
in mice, Morris water maze and polyvalent system for fear-conditioning response. Secondly, we wish to
evaluate the beneficial effect of Ang-(1-7) on the cognitive decline in older mice with diabetes, and will carry
out in vitro studies to determine the reactivity and mitochondrial function in brain arterioles. Thirdly, we wish
to determine HSPC and vascular dysfunctions in a mouse model of Alzheimer’s dementia. Overall, this study
will provide a novel mechanism-based approach for the reversal as well as prevention of vascular cognitive
impairment in older adults with diabetes. We hope that the ‘administrative supplement-research’ would help
us venture into the hypothesis-driven research program with the goal of providing novel mechanism-based
approaches for the treatment of vascular cognitive disorders.
Terms: <21+ years old><AD model><Administrative Supplement><Adult><Adult Human><Adult-Onset Diabetes Mellitus><Aging><Alzheimer><Alzheimer Type Dementia><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease model><Alzheimers Dementia><Alzheimers disease><Ang I (1-7)><AngII><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin II><Angiotensin Receptor><BDNF><Blood Circulation><Blood Precursor Cell><Blood Vessels><Blood flow><Bloodstream><Bone Marrow><Bone Marrow Reticuloendothelial System><Brain><Brain Nervous System><Brain Vascular Disorders><Brain-Derived Neurotrophic Factor><Brittle Diabetes Mellitus><CD143 Antigens><CD34><CD34 gene><Carboxycathepsin><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell Therapy><Cells><Cerebrovascular Circulation><Cerebrovascular Disease><Cerebrovascular Disorders><Cerebrovascular system><Circulation><Clinical><Cognition Disorders><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Development><Diabetes Mellitus><Diabetic mouse><Dipeptidyl Peptidase A><Disturbance in cognition><Dysfunction><Early Intervention><Elderly><Encephalon><Endothelium><Equipment><Evaluation><Functional disorder><Genetic><Goals><HPCA1><Health><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Human><IDDM><Impaired cognition><Impairment><In Vitro><Individual><Injury><Insulin-Dependent Diabetes Mellitus><Intracellular Communication and Signaling><Intracranial Vascular Diseases><Intracranial Vascular Disorders><Investigators><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Ketosis-Resistant Diabetes Mellitus><Kininase A><Kininase II><Maturity-Onset Diabetes Mellitus><Measures><Mice><Mice Mammals><Mitochondria><Modern Man><Murine><Mus><NIDDM><Natural regeneration><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><North Dakota><Pathologic><Pathway interactions><Peptidyl-Dipeptidase A><Pharmacological Treatment><Pharmacology><Physiopathology><Population><Prevalence><Prevention><Primary Senile Degenerative Dementia><Progenitor Cells><Property><Receptor Activation><Receptor Cell><Receptor Protein><Regeneration><Renin-Angiotensin System><Research><Research Personnel><Researchers><Risk><Risk Factors><Signal Transduction><Signal Transduction Systems><Signaling><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Standardization><Stem cells><Sudden-Onset Diabetes Mellitus><System><T1 DM><T1 diabetes><T1D><T1DM><T2 DM><T2D><T2DM><Techniques><Technology><Testing><Type 1 Diabetes Mellitus><Type 1 diabetes><Type 2 Diabetes Mellitus><Type 2 diabetes><Type I Diabetes Mellitus><Type II Diabetes Mellitus><Type II diabetes><Universities><Vascular Cognitive Impairment><Vascular Diseases><Vascular Disorder><Vascular Endothelium><adult onset diabetes><adulthood><advanced age><alzheimer model><angiotensin I (1-7)><angiotensin-(1-7)><arteriole><base><behavior study><behavioral study><biological signal transduction><blood damage><blood stem cell><blood vessel disorder><brain blood flow><brain endothelial cell><brain health><brain microvascular endothelial cell><brain microvasculature><brain microvessels><brain vascular disease><brain vascular dysfunction><brain vascular endothelial cell><brain vasculature><cardiac disease induced cognitive impairment><cardiovascular health><cell mediated therapies><cell-based therapy><cerebral blood flow><cerebral blood vessel><cerebral circulation><cerebral endothelial cell><cerebral microvascular endothelial cell><cerebral microvasculature><cerebral microvessels><cerebral vascular><cerebral vascular disease><cerebral vascular dysfunction><cerebral vascular endothelial cell><cerebral vasculature><cerebro-vascular><cerebrocirculation><cerebrovascular><cerebrovascular blood flow><cerebrovascular dysfunction><cerebrovasculature><cognitive disease><cognitive disorder><cognitive dysfunction><cognitive function><cognitive loss><cognitive performance><cognitive syndrome><conditioned fear><dementia of the Alzheimer type><density><developmental><diabetes><diabetes mouse model><diabetic><elders><experiment><experimental research><experimental study><fear conditioning><geriatric><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><in vivo><insulin dependent diabetes><intracranial vascular dysfunction><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><ketosis resistant diabetes><late life><later life><maturity onset diabetes><meetings><mitochondrial><morris water maze><morris watermaze><mouse model><murine model><neuro-vascular coupling><neurovascular coupling><novel><older adult><older person><overexpress><overexpression><pathophysiology><pathway><preservation><prevent><preventing><primary degenerative 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