Neurocognitive deficits are clearly associated with radiation therapy, particularly in children where they represent a major detrimental side effect of life-saving procedures. Long-standing changes in brain function have also been described in individuals exposed to radiafion in the setting of radiological accidents (e.g Chernobyl). Although not as dramatic or life threatening as the classic syndromes associated with lethal and sub-lethal radiafion exposure, radiafion-induced changes in cognitive capacity will likely present a significant and life-long burden to individuals surviving a radiological accident or nuclear disaster. Accumulating evidence suggests that brain radiafion injury leads to a persistent alteration in the brain's milieu, manifest in animal models over many months as activation of endogenous glial cells, recruitment of peripheral immune cells, and chronic elevation of cytokines, chemokines, and reactive oxygen and nitrogen species. We hypothesize that this neuroinflammatory milieu contributes to neurocognitive deficits, including inhibition of hippocampal neurogenesis and synaptic function. Therefore, a major goal of the proposed studies is to determine whether use of agents that inhibit neuroinflammation and/or production of ROS can mitigate radiation-induced changes in inflammatory cell populations, expression of cytokines, production of ROS, hippocampal neurogenesis, and neurocognitive effects. We will explore this hypothesis in adult mice under two exposure conditions (external and internal radiafion) and in newly born animals where we expect the effects to be enhanced. We will also determine whether radiafion exposed animals are primed for greater neurocognitive deficits following challenge with lipopolysaccharide, a "second hit" known to alter learning and memory. Finally, we will explore the possibility that total body irradiation combined with thermal burn exacerbates central nervous system effects. Specific outcomes of this project will include development of 4 mouse models for investigating the relationship between brain radiation injury and cognitive deficits, as well as testing of three drugs, each acting through a different mechanism to reduce the neuroinflammatory state and potentially restore cognitive capacity.

Public Health Relevance

Brain radiation injury and associated deficits in cognitive function represents one of the most insidious potential outcomes following a radiological accident or nuclear event. Based on the idea that radiafion leads to a neuroinflammatory state that affects brain function, the main goal of this project is to develop models that more closely address radiafion exposure in a disaster setting and test whether drugs that inhibit neuroinflammation can restore normal brain function

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Rochester
United States
Zip Code
Evans, Andrew G; Calvi, Laura M (2015) Notch signaling in the malignant bone marrow microenvironment: implications for a niche-based model of oncogenesis. Ann N Y Acad Sci 1335:63-77
Frisch, Benjamin J; Calvi, Laura M (2014) Hematopoietic stem cell cultures and assays. Methods Mol Biol 1130:315-24
Niswander, Lisa M; Fegan, Katherine H; Kingsley, Paul D et al. (2014) SDF-1 dynamically mediates megakaryocyte niche occupancy and thrombopoiesis at steady state and following radiation injury. Blood 124:277-86
Gopal, Radha; Rangel-Moreno, Javier; Fallert Junecko, Beth A et al. (2014) Mucosal pre-exposure to Th17-inducing adjuvants exacerbates pathology after influenza infection. Am J Pathol 184:55-63
Gao, Feng; Fish, Brian L; Szabo, Aniko et al. (2014) Enhanced survival from radiation pneumonitis by combined irradiation to the skin. Int J Radiat Biol 90:753-61
O'Banion, M Kerry (2014) Does peripheral inflammation contribute to Alzheimer disease? Evidence from animal models. Neurology 83:480-1
Hoffman, Corey M; Calvi, Laura M (2014) Minireview: complexity of hematopoietic stem cell regulation in the bone marrow microenvironment. Mol Endocrinol 28:1592-601
Cherry, Jonathan D; Olschowka, John A; O'Banion, M Kerry (2014) Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation 11:98
Gopal, Radha; Monin, Leticia; Slight, Samantha et al. (2014) Unexpected role for IL-17 in protective immunity against hypervirulent Mycobacterium tuberculosis HN878 infection. PLoS Pathog 10:e1004099
Gopal, Radha; Monin, Leticia; Torres, Diana et al. (2013) S100A8/A9 proteins mediate neutrophilic inflammation and lung pathology during tuberculosis. Am J Respir Crit Care Med 188:1137-46

Showing the most recent 10 out of 21 publications