Whole brain irradiation (WBI) leads to progressive dementia in ~50% of brain tumor patients who survive long- term after treatment, at least in part, due to dysregulation of CBF. Although the specific mechanisms for WBI- induced deceases in CBF and cognitive decline are not yet known, there is increasing evidence that alterations of the neurovascular unit play a crucial role. The objective of this proposal is to elucidate the mechanistic role of irradiation-induced astrocyte dysfunction in cognitive impairment. The central hypothesis is that irradiation causes astrocyte senescence and subsequent dysfunction, altering the production of vasodilator mediators and impairing neurovascular coupling (NVC) responses. The resulting neurovascular dysfunction contributes to decline in CBF and cognitive impairments. The proposed work is novel in that it will be the first to demonstrate that radiation-induced astrocyte senescence is a key driver of the effects of WBI on the brain. The results will likely identify specific mechanisms and reveal potential therapies that are capable of improving cerebral blood supply and restoring learning and memory. The following aims are proposed: 1) Elucidate the cellular mecha- nisms underlying WBI-induced impairment of NVC responses. The working hypothesis is that WBI impairs both eicosanoid-mediated and purinergic components of NVC responses. To test this hypothesis in a clinically rele- vant mouse model of WBI, pathways contributing to NVC responses will be assessed using laser speckle con- trast imaging, pharmacological tools and LC/MS/MS-based measurement of gliotransmitter release. The im- pact of pharmacological up-regulation of NVC responses on cognitive function of WBI-treated mice will be de- termined. 2) Determine how irradiation-induced senescence alters astrocyte function and phenotype. It is pre- dicted that irradiation induces senescence in astrocytes, which impairs cellular energy metabolism and the production/release of ATP and alters the cellular secretory profile, dysregulating the synthesis of vasoactive lipid mediators. To test these hypotheses senescent astrocytes will be isolated from WBI-treated mice and pri- mary human astrocyte cultures will be irradiated in vitro. We will combine advanced cellular imaging tech- niques and cutting-edge proteomics and biochemistry to investigate cellular energetics, gene expression and secretome signatures, the regulation of ATP release and the synthesis of lipid mediators. 3) Determine wheth- er elimination of senescent cells improves NVC and cognitive function in WBI-treated mice. It is hypothesized that activation of p16-dependent cellular senescence programs is responsible for WBI-induced neurovascular dysfunction and cognitive impairment. It is expected that elimination of senescent cells, either through genetic manipulation (p16-3MR mouse model) or by pharmacological means will restore neurovascular function and improve cognition in WBI-treated mice. Together, the proposed studies will identify a fundamental mechanism governing WBI-related neurovascular dysfunction eventually leading to cognitive impairment.

Public Health Relevance

Patients with metastatic brain tumors who are treated with whole brain irradiation (WBI) often experience progressive dementia as a result of this treatment. At the present time, no strategies exist to prevent radiation- induced brain injury and no additional treatments can reverse these effects. Our goal is to understand how radiation damages the brain and to develop effective interventions to maintain learning and memory in these cancer survivors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS100782-02
Application #
9597243
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Babcock, Debra J
Project Start
2017-12-01
Project End
2022-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Valcarcel-Ares, Marta Noa; Tucsek, Zsuzsanna; Kiss, Tamas et al. (2018) Obesity in Aging Exacerbates Neuroinflammation, Dysregulating Synaptic Function-related Genes and Altering Eicosanoid Synthesis in the Mouse Hippocampus: Potential Role in Impaired Synaptic Plasticity and Cognitive Decline. J Gerontol A Biol Sci Med Sci :
Csipo, Tamas; Fulop, Gabor A; Lipecz, Agnes et al. (2018) Short-term weight loss reverses obesity-induced microvascular endothelial dysfunction. Geroscience :
Ungvari, Zoltan; Yabluchanskiy, Andriy; Tarantini, Stefano et al. (2018) Repeated Valsalva maneuvers promote symptomatic manifestations of cerebral microhemorrhages: implications for the pathogenesis of vascular cognitive impairment in older adults. Geroscience 40:485-496
Tarantini, Stefano; Valcarcel-Ares, M Noa; Yabluchanskiy, Andriy et al. (2018) Nrf2 Deficiency Exacerbates Obesity-Induced Oxidative Stress, Neurovascular Dysfunction, Blood-Brain Barrier Disruption, Neuroinflammation, Amyloidogenic Gene Expression, and Cognitive Decline in Mice, Mimicking the Aging Phenotype. J Gerontol A Biol Sci Med Sci 73:853-863
Ungvari, Zoltan I; Yabluchanskiy, Andriy; Hasko, Gyorgy et al. (2018) Age-dependent cardiovascular effects of sepsis in a murine model of cecal ligation and puncture: implications for the design of interventional studies. Am J Physiol Heart Circ Physiol :
Fulop, Gabor A; Ramirez-Perez, Francisco I; Kiss, Tamas et al. (2018) IGF-1 deficiency Promotes Pathological Remodeling of Cerebral Arteries: A Potential Mechanism Contributing to the Pathogenesis of Intracerebral Hemorrhages in Aging. J Gerontol A Biol Sci Med Sci :
Reagan, Alaina M; Gu, Xiaowu; Paudel, Sijalu et al. (2018) Age-related focal loss of contractile vascular smooth muscle cells in retinal arterioles is accelerated by caveolin-1 deficiency. Neurobiol Aging 71:1-12
Ahn, Bumsoo; Pharaoh, Gavin; Premkumar, Pavithra et al. (2018) Nrf2 deficiency exacerbates age-related contractile dysfunction and loss of skeletal muscle mass. Redox Biol 17:47-58
Fulop, Gabor A; Kiss, Tamas; Tarantini, Stefano et al. (2018) Nrf2 deficiency in aged mice exacerbates cellular senescence promoting cerebrovascular inflammation. Geroscience 40:513-521
Szarka, Nikolett; Pabbidi, Mallikarjuna R; Amrein, Krisztina et al. (2018) Traumatic Brain Injury Impairs Myogenic Constriction of Cerebral Arteries: Role of Mitochondria-Derived H2O2 and TRPV4-Dependent Activation of BKca Channels. J Neurotrauma :

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