Neurocognitive deficits are cleariy associated with radiation therapy, particulariy 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 alterafion in the brain's milieu, manifest in animal models over many months as acfivafion 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 neurocognifive deficits, including inhibifion of hippocampal neurogenesis and synapfic function. Therefore, a major goal of the proposed studies is to determine whether use of agents that inhibit neuroinfiammafion and/or producfion of ROS can mifigate radiation-induced changes in infiammatory cell populafions, expression of cytokines, producfion of ROS, hippocampal neurogenesis, and neurocognitive effects. We will explore this hypothesis in adult mice under two exposure condifions (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 investigafing the relafionship between brain radiation injury and cognitive deficits, as well as tesfing of three drugs, each acfing through a different mechanism to reduce the neuroinflammatory state and potentially restore cognitive capacity.

Public Health Relevance

Brain radiation injury and associated deflcits in cognitive funcfion 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 funcfion, 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 neuroinfiammation can restore normal brain funcfion.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI091036-03
Application #
8381727
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$386,811
Indirect Cost
$114,448
Name
University of Rochester
Department
Type
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Begolly, Sage; Olschowka, John A; Love, Tanzy et al. (2017) Fractionation enhances acute oligodendrocyte progenitor cell radiation sensitivity and leads to long term depletion. Glia :
Judge, Jennifer L; Lacy, Shannon H; Ku, Wei-Yao et al. (2017) The Lactate Dehydrogenase Inhibitor Gossypol Inhibits Radiation-Induced Pulmonary Fibrosis. Radiat Res 188:35-43
Domingo-Gonzalez, Racquel; Das, Shibali; Griffiths, Kristin L et al. (2017) Interleukin-17 limits hypoxia-inducible factor 1? and development of hypoxic granulomas during tuberculosis. JCI Insight 2:
Sweet, Tara B; Hurley, Sean D; Wu, Michael D et al. (2016) Neurogenic Effects of Low-Dose Whole-Body HZE (Fe) Ion and Gamma Irradiation. Radiat Res 186:614-623
Moravan, Michael J; Olschowka, John A; Williams, Jacqueline P et al. (2016) Brain radiation injury leads to a dose- and time-dependent recruitment of peripheral myeloid cells that depends on CCR2 signaling. J Neuroinflammation 13:30
Begolly, Sage; Shrager, Peter G; Olschowka, John A et al. (2016) Fractionation Spares Mice From Radiation-Induced Reductions in Weight Gain But Does Not Prevent Late Oligodendrocyte Lineage Side Effects. Int J Radiat Oncol Biol Phys 96:449-457
Groves, Angela M; Johnston, Carl J; Misra, Ravi S et al. (2016) Effects of IL-4 on pulmonary fibrosis and the accumulation and phenotype of macrophage subpopulations following thoracic irradiation. Int J Radiat Biol 92:754-765
Rabender, Christopher; Mezzaroma, Eleonora; Mauro, Adolfo G et al. (2016) IPW-5371 Proves Effective as a Radiation Countermeasure by Mitigating Radiation-Induced Late Effects. Radiat Res 186:478-488
Williams, Jacqueline P; Calvi, Laura; Chakkalakal, Joe V et al. (2016) Addressing the Symptoms or Fixing the Problem? Developing Countermeasures against Normal Tissue Radiation Injury. Radiat Res 186:1-16
Barlow, Margaret L; Cummings, Ryan J; Pentland, Alice P et al. (2016) Total-Body Irradiation Exacerbates Dissemination of Cutaneous Candida Albicans Infection. Radiat Res 186:436-446

Showing the most recent 10 out of 61 publications