Therapeutic irradiation is commonly used to treat both primary and metastatic brain tumors and can cause a number of late effects including progressive cognitive dysfunction. There is no treatment currently available that can even partially reverse cognitive changes observed after radiation injury. Specifically, irradiation of the temporal lobe can profoundly affect the cellular structures mediating learning and memory. Ionizing radiation has also been consistently shown to activate several neuroinflammatory signaling cascades that can impact multiple neural processes and synaptic transmission ultimately causing disruptions in hippocampal function. Notably, resident microglia and infiltrating monocytes, the key cellular player in neuroinflammatory processes, have distinct embryological origins and also fulfill different functions. The mechanism/s by which activation of the inflammatory response affect cognitive functions after brain irradiation and the specific role of different myeloid cells remain elusive. Thus, there is a clear need to understand the mechanisms of radiation injury and inflammation to develop strategies for preventing cognitive decline following cranial irradiation. Recent work from our group during the previous funding period has shed light in these questions and revealed specific problems in the cellular and molecular mechanisms underlying radiation-induced memory deficits. Specifically our data demonstrates a direct link between CCL2/CCR2 and cognition. These results provide a mechanistic link between peripheral innate immune system and cognition after brain irradiation. In the current proposal we will evaluate the central hypothesis that therapeutic doses of cranial irradiation induce infiltration of peripheral monocytes that modifies the resident inflammatory response and promotes synaptic dysfunction and long term cognitive deficits.
Aim 1 : Determine the kinetics and inflammatory phenotype of radiation-induced myeloid cell alterations after single and hypofractionated therapeutic doses of irradiation.
Aim 2 : Evaluate the role of peripheral monocyte recruitment into the brain as a mechanistic driver of radiation-induced altered synaptic and cognitive functions.
Aim 3 : Determine if temporary depletion of myeloid cells prevent the loss of synaptic function and cognition after single and hypofractionated doses of radiation. Very little is known in regard to the evolution of radiation induced pathophysiology in the context of peripherally derived macrophage accumulation or inflammation, and how this relates to altered synaptic and cognitive function. Our final therapeutic goal is to modify the cognitive changes observed after radiation injury.

Public Health Relevance

Therapeutic irradiation is commonly used to treat both primary and metastatic brain tumors and can cause a number of late effects including progressive cognitive dysfunction. There is no treatment currently available that can even partially reverse cognitive changes observed after radiation injury and our data demonstrates a direct link between CCL2/CCR2 and cognition. The proposed research employs: (1) a unique animal genotype that allows discrimination between resident (CX3CR1GFP/+) and peripheral (CCR2RFP/+) myeloid cells, (2) genetic (CCR2RFP/RFP mice), (mGFAPCre/CCL2flx/flx/RosaEYFP) and (3) pharmacological (novel phase I and II pharmacotherapeutic treatments) approaches to examine the neuroinflammatory response in the irradiated brain. Our proposed studies will identify immune related factors as potentially critical contributors to the susceptibility of the radiation-induced loss of cognitive function. Our final therapeutic goal is to modify the cognitive changes observed after radiation injury.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA213441-02
Application #
9397533
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Prasanna, Pat G
Project Start
2016-12-09
Project End
2021-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Physical Medicine & Rehab
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Feng, Xi; Krukowski, Karen; Jopson, Timothy et al. (2017) Delayed-matching-to-place Task in a Dry Maze to Measure Spatial Working Memory in Mice. Bio Protoc 7: