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.

R01NS056218

2006-07-01

2019-03-31