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Principal Investigator: Sanna Darvish
Organization: UNIVERSITY OF COLORADO
Fiscal Year: 2024
Award: $42,030
Funding agency: National Institute on Aging
PROJECT SUMMARY/ABSTRACT
The purpose of this Ruth L. Kirschstein National Research Service Award is to provide support for Ms.
Sanna Darvish, a PhD student in Dr. Douglas Seals’ laboratory at the University of Colorado Boulder, to
conduct research that will prepare her to become an independent investigator in the field of cerebrovascular
aging. As part of her proposed training plan, she will learn a variety of new technical, conceptual, intellectual,
and professional skills and refine research skills currently under development. To do so, she will add
outcomes to an ongoing NIH R01-funded clinical trial led by her Sponsor to investigate the efficacy of the
mitochondrial-targeted antioxidant, MitoQ, for improving cerebrovascular function in older adults and the
mechanism(s) of action. She will also assess the effects of MitoQ on fluid cognitive function. Cardiovascular
diseases (CVD) are the leading cause of mortality in the U.S. Cerebrovascular diseases represent 37% of all
CVD and, when considered alone, are the 5th most common cause of death. Aging is the primary risk factor for
CVD, cerebrovascular diseases, Alzheimer’s disease and related dementias. Decreased cerebrovascular
function (i.e., reduced cerebrovascular reactivity [CVR] and cerebral blood flow) is a key mechanism
contributing to the age-related increase in risk for these diseases and is mediated in part by decreases in the
vasodilatory molecule nitric oxide (NO), leading to cerebral endothelial cell (EC) dysfunction. Excessive
reactive oxygen species production by mitochondria (mtROS) is an important contributor to
cerebrovascular dysfunction as mtROS can scavenge NO and impair EC function. As such, establishing novel
strategies to decrease mtROS to improve cerebrovascular function in older adults is an important biomedical
research priority. Supported by a strong scientific premise and compelling preliminary results, Ms. Darvish
will use innovative translational approaches to determine if three months of MitoQ treatment (versus placebo;
n=30/group) in older adults (60 years of age) Aim 1) improves cerebrovascular function; Aim 2) if the
improvements are mediated by a) reductions in tonic suppression of cerebrovascular function by mtROS, and
b) beneficial changes in the circulating milieu that improve cerebral EC function; and Aim 3) if MitoQ improves
fluid cognition and if improvements are associated with enhanced cerebrovascular function. The proposed
research will be the first to assess the efficacy of MitoQ treatment for improving cerebrovascular function in
older adults, a group at elevated risk for cerebrovascular diseases, Alzheimer’s disease and related
dementias. This F31 fellowship project addresses important NIA research priorities to: 1) identify effective
interventions aimed at preventing age-related diseases, and 2) investigate biological mechanism(s)
involved in aging using translational, systems-based approaches. Under the supervision of her mentors, Ms.
Darvish will complete the proposed research and training plan to advance an independent line of
investigation and facilitate development towards becoming a successful independent scientific investigator.
Terms: <AD related dementia><ADRD><Acetylcholine><Active Oxygen><Acute><Address><After Care><After-Treatment><Aftercare><Age Years><Aging><Alzheimer's and related dementias><Alzheimer's disease and related dementia><Alzheimer's disease and related disorders><Alzheimer's disease or a related dementia><Alzheimer's disease or a related disorder><Alzheimer's disease or related dementia><Alzheimer's disease related dementia><Amentia><Antioxidants><Area><Bioavailability><Biochemical><Biological><Biological Availability><Biomedical Research><Blood Flow Velocity><Blood Plasma><Blood Vessels><Brain Vascular><Brain Vascular Disorders><Brain Vascular reactivity><Cardiovascular Diseases><Cause of Death><Cell Function><Cell Physiology><Cell Process><Cellular Function><Cellular Physiology><Cellular Process><Cerebral endothelium><Cerebrovascular Circulation><Cerebrovascular Disease><Cerebrovascular Disorders><Cerebrovascular system><Chronic><Clinical Trials><Clinical Trials Design><Cognition><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Colorado><Cross-Over Designs><Crossover Design><Data><Dementia><Development><Disturbance in cognition><Dose><Double-Blind Method><Double-Blind Study><Double-Blinded><Double-Masked Method><Double-Masked Study><Dysfunction><Elderly><Endogenous Nitrate Vasodilator><Endothelial Cells><Endothelium><Endothelium-Derived Nitric Oxide><Enrollment><Exposure to><Fellowship><Functional disorder><Funding><Human><Hypercapnia><Impaired cognition><Impairment><Infrastructure><Internal Carotid Artery><Internal carotid artery structure><Intracranial Vascular Diseases><Intracranial Vascular Disorders><Investigation><Investigators><Laboratories><Learning><Liquid substance><Measurement><Measures><Mediating><Mentors><Mitochondria><Mitochondrial Matrix><Modern Man><Mononitrogen Monoxide><NIH><NRSA><National Institutes of Health><National Research Service Awards><Nitric Oxide><Nitrogen Monoxide><Nitrogen Protoxide><Oral><Outcome><Oxidative Stress><Oxygen Radicals><Parents><Peripheral><Ph D student><Ph D. student><Ph. D. student><Ph.D student><Ph.D. student><PhD student><PhD. student><Physiologic Availability><Physiopathology><Placebo Control><Placebos><Plasma><Plasma Serum><Position><Positioning Attribute><Pro-Oxidants><Production><R-Series Research Projects><R01 Mechanism><R01 Program><Randomized><Reactive Oxygen Species><Research><Research Grants><Research Personnel><Research Priority><Research Project Grants><Research Projects><Researchers><Rest><Reticuloendothelial System, Serum, Plasma><Risk><Risk Factors><Sham Treatment><Subcellular Process><Supervision><Supplementation><System><Trail Making Test><Training><Translating><Treatment Period><United States National Institutes of Health><Universities><advanced age><age associated><age associated disease><age associated disorder><age associated effects><age associated impairment><age correlated><age dependent><age dependent disease><age dependent disorder><age dependent impairment><age effect><age linked><age related><age related effects><age related human disease><age specific><age-related disease><age-related disorder><age-related impairment><aged group><aged groups><aged individual><aged individuals><aged mice><aged mouse><aged people><aged person><aged persons><aged population><aged populations><aging effect><aging population><biologic><blood flow in brain><blood vessels in the brain><brachial artery><brain blood circulation><brain blood flow><brain blood vessels><brain endothelial cell><brain endothelium><brain microvascular endothelial cell><brain vascular disease><brain vascular dysfunction><brain vascular endothelial cell><brain vasculature><carbon dioxide retention><cardiovascular disorder><cardiovascular risk><cardiovascular risk factor><cerebral blood flow><cerebral blood vessel><cerebral circulation><cerebral endothelial cell><cerebral microvascular endothelial cell><cerebral vascular><cerebral vascular disease><cerebral vascular dysfunction><cerebral vascular endothelial cell><cerebral vascular reactivity><cerebral vasculature><cerebro-vascular><cerebrocirculation><cerebrovascular><cerebrovascular blood flow><cerebrovascular dysfunction><cerebrovascular reactivity><cerebrovascular vessels><cerebrovasculature><cognitive dysfunction><cognitive function><cognitive loss><cognitive performance><cortical endothelium><determine efficacy><developmental><disease risk><disorder risk><doctoral student><effective intervention><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><elderly mice><elevated carbon dioxide><endothelial cell derived relaxing factor><endothelial dysfunction><enroll><evaluate efficacy><examine efficacy><executive control><executive function><fluid><geriatric><graduate student><hypercarbia><impact of age><improved><in vivo><increased level Carbon dioxide><influence of age><innovate><innovation><innovative><insight><intracranial vascular dysfunction><liquid><mitochondrial><mortality><new approaches><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel approaches><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><old mice><older adult><older adulthood><older men><older women><parent><pathophysiology><placebo controlled><population aging><post treatment><prevent><preventing><processing speed><randomisation><randomization><randomly assigned><response><seal><senior citizen><sham therapy><skills><translation strategy><translational approach><translational strategy><treatment days><treatment duration><vascular><vascular endothelial dysfunction>