This is Beeson Career Development Award application designed to provide Dr. Anna Csiszar with additional training related to neurocognitive function at the Reynolds Oklahoma Center on Aging. Dr. Csiszar is an outstanding, well published candidate and the additional training will provide expertise in behavioral analyses, neurostereology, and cerebrovascular analyses necessary for her to achieve independence. Cognitive function decreases with age even in the absence of overt pathological processes. This decline in cognitive function clearly diminishes quality of life, is a major factor in loss of independence, and imparts a costly burden to society as a whole and to the medical health care system in particular. Previous studies demonstrated that age-related cerebrovascular rarefaction and microvascular dysfunction impair hippocampal blood flow, which has an etiologic role in cognitive decline during aging. The goal of this proposal is to identify key cellular mechanisms that can be targeted therapeutically to prevent/reverse age-related cerebral microvascular alterations maintaining normal hippocampal blood flow and protecting neurocognitive function. The direction and hypotheses of this application emerge from key findings that caloric restriction (CR) and the CR mimetic resveratrol have the potential to beneficially impact vascular physiology in aged mammals. We propose to test the hypothesis that caloric restriction protects the cerebral microvasculature from the deleterious effects of oxidative stress associated with aging, via induction of the Nrf2/ARE- regulated ROS detoxification systems. We posit that pharmacological activation of this pathway in endothelial cells (with resveratrol or sulforaphane) mimics the effects of caloric restriction, which contribute significantly to an intervention strategy for protection of neurocognitive function during aging. The following aims are proposed: 1) Assess whether CR and CR mimetics can delay/prevent the age-associated decline in cerebral regional blood flow, the reduction in capillary and arteriolar density and angiogenesis, and the decline in spatial learning and memory and determine whether genetic depletion of Nrf2 abrogates the microvascular protective effects of CR and resveratrol treatment. 2) Determine whether CR and CR mimetics can delay/prevent age-associated microvascular oxidative stress and impairment of local vasoregulatory mechanisms via induction of Nrf2/ARE-dependent antioxidant systems. 3) Determine whether systemic factors induced by CR in aged animals confer anti-oxidative, anti-apoptotic and pro-angiogenic effects on cerebral microvascular endothelial cells. Cultured endothelial cells will be treated with sera from ad libitum or CR fed animals and cellular ROS production, angiogenic potential and resistance to oxidative stress-induced apoptosis will be assessed. The role of Nrf2 activation in the protective effects of CR sera treatment will be elucidated. The proposed studies will provide the first comprehensive analysis of the role of the Nrf2/ARE pathway in maintaining a youthful cerebral microvascular phenotype during CR and will provide novel and definitive information on novel approaches to prevent/reverse cerebrovascular dysfunction and functional changes in the brain with age that are precursors to age-related disease, loss of cognitive function and the increased risk of dementia.
A decline in cognitive function clearly diminishes quality of life, is a major factor in loss of independence, and imparts a costly burden to society as a whole and to the medical health care system in particular. The age-related impairment of cerebral blood supply significantly contributes to cognitive decline in the elderly. The goal of this project is to identify novel molecular targets that can be activated pharmacologically to protect the cerebral blood vessels from free radical mediated injury and thus to improve cerebral blood flow and cognitive function in elderly patients. We will test the hypotheses that in the vascular system a protein named Nrf2 mediates multifaceted vasoprotective effects. We posit that treatment with Nrf2-activating molecules, or inducing Nrf2 by dietary restriction can exert significant cerebral vasoprotective effects protecting cognitive function in aged mice.
|Gardner, Andrew W; Parker, Donald E; Montgomery, Polly S et al. (2015) Gender and racial differences in endothelial oxidative stress and inflammation in patients with symptomatic peripheral artery disease. J Vasc Surg 61:1249-57|
|Toth, Peter; Tarantini, Stefano; Tucsek, Zsuzsanna et al. (2014) Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and downregulation of NADPH oxidase. Am J Physiol Heart Circ Physiol 306:H299-308|
|Yan, Han; Mitschelen, Matthew; Toth, Peter et al. (2014) Endothelin-1-induced focal cerebral ischemia in the growth hormone/IGF-1 deficient Lewis Dwarf rat. J Gerontol A Biol Sci Med Sci 69:1353-62|
|Csiszar, Anna; Gautam, Tripti; Sosnowska, Danuta et al. (2014) Caloric restriction confers persistent anti-oxidative, pro-angiogenic, and anti-inflammatory effects and promotes anti-aging miRNA expression profile in cerebromicrovascular endothelial cells of aged rats. Am J Physiol Heart Circ Physiol 307:H292-306|
|Tucsek, Zsuzsanna; Toth, Peter; Tarantini, Stefano et al. (2014) Aging exacerbates obesity-induced cerebromicrovascular rarefaction, neurovascular uncoupling, and cognitive decline in mice. J Gerontol A Biol Sci Med Sci 69:1339-52|
|Csiszar, Anna; Tucsek, Zsuzsanna; Toth, Peter et al. (2013) Synergistic effects of hypertension and aging on cognitive function and hippocampal expression of genes involved in *-amyloid generation and Alzheimer's disease. Am J Physiol Heart Circ Physiol 305:H1120-30|
|Ungvari, Zoltan; Tucsek, Zsuzsanna; Sosnowska, Danuta et al. (2013) Aging-induced dysregulation of dicer1-dependent microRNA expression impairs angiogenic capacity of rat cerebromicrovascular endothelial cells. J Gerontol A Biol Sci Med Sci 68:877-91|
|Toth, Peter; Csiszar, Anna; Sosnowska, Danuta et al. (2013) Treatment with the cytochrome P450 ýý-hydroxylase inhibitor HET0016 attenuates cerebrovascular inflammation, oxidative stress and improves vasomotor function in spontaneously hypertensive rats. Br J Pharmacol 168:1878-88|
|Toth, Peter; Tucsek, Zsuzsanna; Sosnowska, Danuta et al. (2013) Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension. J Cereb Blood Flow Metab 33:1732-42|
|Ungvari, Zoltan; Csiszar, Anna; Sosnowska, Danuta et al. (2013) Testing predictions of the oxidative stress hypothesis of aging using a novel invertebrate model of longevity: the giant clam (Tridacna derasa). J Gerontol A Biol Sci Med Sci 68:359-67|
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