Whole brain irradiation (WBI) leads to progressive dementia in approximately 20-50% of brain tumor patients who survive long-term after treatment. At the present time, no strategies exist to prevent radiation- induced brain injury, and no additional treatments can reverse these effects. Our overall goal is to develop therapeutic interventions that ameliorate the effects of radiation-induced cognitive impairment. Our research studies are unique since we use clinically relevant, fractionated doses of WBI allowing us to make conclusions related to the etiology of cognitive dysfunction that occurs in response to WBI. During our first funding cycle, we found that radiation-induced cellular senescence is a potential mechanism that contributes to vascular and cognitive dysfunction and that bone marrow transplants can reverse radiation-induced cognitive impairment. We postulated that bone marrow transplants modify the cerebrovascular microenvironment, reducing the impact of cellular senescence and permit regulated cell proliferation. Our results are consistent with the results of previous studies investigating the effects of radiation on cellular senescence, but we have made important strides in incorporating these findings into the etiology of both cerebrovascular and cognitive dysfunction that occur after radiation therapy. These results have led to our current hypothesis that fractionated WBI induces a senescent phenotype that alters the cerebral microenvironment. Our work is novel in that we will be the first to demonstrate that radiation-induced cellular senescence is a unifying concept for the actions of radiation on the brain. This work will likely lead to the identification of target mechanisms for interventions thos are capable of restoring cognitive function. We will examine this hypothesis by the experiments proposed for the following specific aims: 1) Determine whether senescence and acquisition of a senescence-associated secretory phenotype (SASP) contribute to the impaired angiogenic response of cerebral microvessels;2) Determine whether whole brain radiation impairs cerebrovascular autoregulatory responses, impairs blood flow and/or disrupts blood-brain barrier function;3) Identify the mechanisms for the increase in vascular density and recovery of learning and memory after bone marrow transplantation. Our previous studies of radiation-induced cellular senescence in endothelial cells and the effects of bone marrow transplants that restore both vascular proliferation and cognitive function after WBI provide key support for our application.

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 #
2R01NS056218-07A1
Application #
8697346
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Babcock, Debra J
Project Start
2006-07-01
Project End
2019-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
7
Fiscal Year
2014
Total Cost
$357,599
Indirect Cost
$115,978
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
73117
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