Little is known about the duration, causes, or mechanisms underlying the enduring and prevalent consequences of a previous cancer experience on the brain and behavior. The long-term goal for this work is to determine how cancer outside of the CNS affects brain physiology and, therefore, brain function, both during cancer and after successful cancer resolution. The overall objective of this R03 project, as the first step in pursuit of our long-term goal, is to harvest preliminary data for the succeeding NCI R01 application and to develop an innovative extension of established tumor model methodology by creating a tumor resected survivor mouse mod- el. The central hypothesis for this project is that mouse mammary tumors induce microglial-mediated neuroinflammation and impair learning and memory, both of which are ameliorated by tumor resection.
Two specific aims are proposed to test the central hypothesis using a non-metastatic mouse model of breast cancer and breast cancer survival (i.e., complete tumor resection).
Aim 1 is to identify alterations in cognitive behavior during tumor development and post-tumor resection. Based on our preliminary data, the working hypothesis is that peripheral tumors induce specific learning and memory impairments as measured by standardized rodent behavioral tests, whereas tumor resection attenuates these impairments.
Aim 2 will determine neural alterations relevant to cognition and coincident with tumor growth or following tumor resection. The working hypothesis for this aim is that peripheral tumors trigger microglial-mediated neuroinflammation (e.g., elevations in pro- inflammatory cytokines, NF-?B, indolamine-2,3-deoxygenase mRNA and protein expression and activated microglial morphology) coincident with learning and memory impairments. The expected outcome for Aim 1 is the identification of specific types or components of cognitive behavior that are influenced solely by the presence of an extra-CNS tumor or which remain after tumor resection using a new tumor model.
Aim 2 will provide the foundation for the mechanistic neural pathways underlying these behavioral changes. This contribution will be significant because it will provide insight into neuroinflammation-specific targets of intervention for cancer- and survivor-associated cognitive problems, which is not possible with human research. The proposed research is innovative, in our opinion, because it establishes a model of mammary cancer survivorship by which to investigate questions relevant to the rapidly expanding population of cancer survivors. The proposed research is also innovative because it will begin to delineate the roles of cancer, cancer treatment, and cancer-associated stress in cognitive changes related to cancer.
The proposed research is relevant to public health because it will elucidate potential mechanistic targets of intervention underlying the negative consequences of cancer and cancer survivorship on brain function. Consistent with the goals of NCI, the positive impact that this work will make includes reducing cancer-related co-morbidities, which in turn, will reduce hospital costs and improve patient and survivor quality of life.
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