Chemotherapy-induced vascular cognitive impairment: role of endothelial senescence
Description: Studies on cancer survivors show that chemotherapy induces long-lasting adverse effects on cognitive function. Importantly, no strategies exist to prevent chemotherapy-induced cognitive impairment (CICI). Progress on this field is hampered by the lack of adequately controlled clinical studies. Research on animal models, which allow for a more stringent control of confounding factors and elucidation of cellular and molecular mechanisms are needed. We have established an innovative mouse model, cancer-free p16-3MR mice treated with the chemotherapeutic drug paclitaxel (PTX), which allows the detection and elimination of senescent cells. We discovered that PTX induces senescence in cerebromicrovascular endothelial cells (CMVECs), a common DNA damage response. Although chemotherapeutics doesn¿t cross the blood brain barrier and their brain concentration is very low, endothelial cells are exposed to the highest concentrations of these drugs making them uniquely vulnerable to loss of function. Endothelial cells play critical roles both in regulation of basal CBF and moment-to-moment adjustment of CBF to neuronal activity via neurovascular coupling (NVC). NVC responses are critical for healthy brain function and our recent studies demonstrate that impaired NVC is causally related to cognitive decline. The central hypothesis of this application is that chemotherapeutic agents cause endothelial senescence, which impairs CBF and endothelium-dependent NVC responses contributing to CICI. Our work is novel in that it will be the first to demonstrate that chemotherapy-induced endothelial senescence is a critical contributing factor to the development of CICI. Specific Aims: 1) Demonstrate the mechanistic role of chemotherapy-induced endothelial senescence in dysregulation of CBF. We postulate that chemotherapy induces senescence in endothelial cells, impairing endothelial vasodilator function, compromising NVC responses and decreasing capillary density in the senescence reporter mouse model (p16-3MR mice). 2) Demonstrate the mechanistic role of chemotherapy-induced senescence in cognitive decline. Our hypothesis is that PTX-induced senescence contributes to impairment of multiple domains of cognition. Our prediction is that elimination of senescent cells will prevent the development of CICI. Our expected outcomes will generate an integrated understanding of the mechanisms that underlie cerebral blood flow dysregulation after chemotherapy.
Funder: American Heart Association
Amount: $62,030
Funding type: training
Funder scheme: Predoctoral Fellowship
Start date: 2020-01-01
End date: 2021-12-31
Investigators: Chetan Ahire, Chetan Ahire
Institution: University of Oklahoma Health Sciences Center
Funded outputs count: 1
Funder award ID: 20PRE35211043
OpenAlex ID: G1204878802