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Chemotherapy-induced vascular cognitive impairment: role of endothelial senescence

Award Number: R01CA255840
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Chemotherapy-induced vascular cognitive impairment: role of endothelial senescence - Project Summary 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $331,688 )
2025	2025	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	000	5	12/17/2024	NON-COMPETING CONTINUATION	$298,519
2025	2025	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	001	5	6/2/2025	NON-COMPETING CONTINUATION	$33,169
														Subtotal = $331,688

Issue Date FY: 2024 ( Subtotal = $315,104 )
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$16,585
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	000	4	12/8/2023	NON-COMPETING CONTINUATION	$298,519
														Subtotal = $315,104

Issue Date FY: 2023 ( Subtotal = $325,054 )
2023	2023	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	000	3	2/9/2023	NON-COMPETING CONTINUATION	$325,054
														Subtotal = $325,054

Issue Date FY: 2022 ( Subtotal = $325,054 )
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	000	2	12/10/2021	NON-COMPETING CONTINUATION	$298,519
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	001	2	4/28/2022	NON-COMPETING CONTINUATION	$26,535
														Subtotal = $325,054

Issue Date FY: 2021 ( Subtotal = $331,688 )
2021	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Treatment Research	000	1	1/1/2021	NEW	$331,688
														Subtotal = $331,688

Grand Total All Awards = $1,628,588

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Chemotherapy-induced vascular cognitive impairment: role of endothelial senescence

Award Number: R01CA255840

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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