Many long-term survivors of cancer experience progressive chemotherapy-induced cognitive impairment (CICI, commonly referred to as chemobrain). Importantly, no strategies exist to prevent/reverse CICI. Chemotherapeutics do not cross the blood brain barrier and mature neurons are resistant to chemotherapeutic agents. In contrast, endothelial cells are exposed to the highest concentrations of these drugs and are highly sensitive to their effects. We discovered that chemotherapeutic drugs, including paclitaxel (PTX) induce cerebromicrovascular endothelial cells to undergo cellular senescence, a common DNA damage response. Endothelial cells play critical roles in regulation of basal CBF, moment-to-moment adjustment of CBF to neuronal activity via neurovascular coupling (NVC) and maintenance of the microcirculatory network. Each of these endothelial functions are critical for healthy brain function. The central hypothesis of this application is that chemotherapeutic agents induce endothelial senescence, which impairs cerebral blood flow, promote microvascular rarefaction and compromise endothelium-dependent neurovascular coupling responses and barrier integrity contributing to CICI. This hypothesis will be tested using an innovative mouse model: cancer- free senescence reporter mice treated with the chemotherapeutic drug paclitaxel (PTX), which allows the detection and selective elimination of senescent cells.
Specific Aims : 1) Deter?mine how chemotherapy-induced endothelial sen?escence alters neurovascular coup?ling resp?onses and CBF. We postulate that chemotherapy induces senescence in endothelial cells, which impairs endothelial vasodilator function, compromises endothelium-dependent NVC responses and decreases capillary density, dysregulating CBF. Our prediction, based on this hypoth?esis, is that elimination of senesc?ent endothelial cells, through genetic manipulation or through translatable senolytic therapies w?ill restore neurovascular fun?ction and improve CBF in mice treated with clinically relevant PTX protocol. 2) Deter?mine how chemotherapy-induced endothelial sen?escence impacts microvascular density. We postulate that chemotherapy -induced endothelial senescence compromises the maintenance of the microcirculatory network and/or impairs endothelial barrier function and that elimination of senesc?ent cells w?ill increase cerebromicrovascular density and restore barrier function, attenuating neuroinflammation. 3) Deter?mine how chemotherapy-induced endothelial sen?escence impacts cognitive function. We postulate that PTX-induced microvascular dysfunction contribute to the impairment of multiple domains of cognition and that elimination of senescent cells will prevent/delay the development of CICI. Our expected outcomes will generate an integrated understanding of the mechanisms that underlie microvascular dysfunction after chemotherapy and establish endothelial senescence as a translationally relevant target for prevention of CICI.
The proposed research is relevant to public health as cancer treatment with chemotherapeutic drugs induces progressive, long-lasting adverse effects on cognitive function in 30 to 50% of patients, yet its pathogenesis is not well understood. Increasing clinical and experimental evidence suggest that chemotherapeutic agents cause cerebral vascular damage, which impairs cerebral blood flow and vascular responses contributing to chemotherapy-induced cognitive impairment. The discovery of the cellular mechanisms responsible for decreased cognitive capacity after cancer treatment is ultimately expected to enhance understanding of the pathogenesis of the disease and will lead to the development of novel therapeutic interventions for prevention; thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of cancer.