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Adiponectin on cerebrovascular regulation in vascular cognitive impairment and dementia (VCID)

Award Number: R01NS124673
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Vascular insufficiency underlies the pathogenesis of vascular cognitive impairment and dementia (VCID). The pathological events in VCID involves crosstalk between the CNS and peripheral metabolic regulation, yet the details in bridging two compartments are underexplored. To fill this gap, the present proposal focuses on the impact of the adiponectin in the progression of VCID. Adiponectin is an adipokine mainly produced by adipocytes and secreted into the bloodstream, regulating glucose metabolism and fatty acid oxidation. Using a mouse model of chronic cerebral hypoperfusion-induced VCID by asymmetric common carotid artery stenosis (ACAS), we found that adiponectin levels increased in plasma 3d to 42d after ACAS, yet were suppressed in cerebrospinal fluid at 42d after ACAS. We obtained further promising data showing that 1) Adiponectin knockout (KO) mice exhibited more prominent cognitive deficits up to 42d after ACAS, whereas administration of adipoRon, a small-molecule agonist of adiponectin receptor (adipoR), rescued long-term cognitive functions in adiponectin KO mice and attenuated cognitive deficits in wild-type mice; 2) Adiponectin KO exacerbated, while adipoRon treatment improved long-term white matter structural and functional integrity; 3) Adiponectin receptors AdipoR1/R2 were highly expressed on endothelial cells (ECs); 4) Adiponectin KO exacerbated the reduction in cortical cerebral blood flow (CBF) after ACAS; 5) AdipoRon promotes endothelial nitric oxide synthase activation in cultured EC; 6) AdipoRon reduced blood brain barrier (BBB) leakage in vivo after ACAS and protected from oxygen-glucose deprivation (OGD)-induced hyperpermeability in an in vitro BBB model. 7) AdipoRon treatment inhibited neuroinflammation after ACAS and inhibited the release of inflammatory factors from primary EC upon OGD. The current proposal will further explore the effects of adiponectin on endothelial function in ACAS, including vasoactivity, BBB integrity, and EC inflammation and will develop in vivo adipoRon regimen as a novel strategy to preserve white matter and improve cognitive function. The central hypothesis is that adiponectin ameliorates cognitive deficits and white matter injury in chronic cerebral hypoperfusion- induced VCID at least in part by enhancing endothelial-dependent vasoactivity and BBB integrity. Aim 1. Test if adiponectin improves endothelial-dependent vasoactivity and CBF by enhancing vascular production of nitric oxide following chronic cerebral hypoperfusion-induced VCID. Aim 2. Test if adiponectin inhibits endothelial inflammation and protects the BBB integrity against hypoperfusion-induced injury. Aim 3. Test if adipoRon treatment maintains white matter integrity and long-term neurological functions after ACAS in young and aged mice of both sexes.


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 = $357,750 )
2025	2025	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/9/2025	NON-COMPETING CONTINUATION	$357,750
														Subtotal = $357,750

Issue Date FY: 2024 ( Subtotal = $385,575 )
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	4/25/2024	NON-COMPETING CONTINUATION	$27,825
2024	2024	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	12/25/2023	NON-COMPETING CONTINUATION	$357,750
2024	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/21/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $385,575

Issue Date FY: 2023 ( Subtotal = $397,500 )
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/23/2022	NON-COMPETING CONTINUATION	$357,750
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/30/2023	NON-COMPETING CONTINUATION	$39,750
2023	2023	UNIVERSITY OF PITTSBURGH - OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	4200 FIFTH AVENUE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	7/5/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $397,500

Issue Date FY: 2022 ( Subtotal = $394,375 )
2022	2022	UNIVERSITY OF PITTSBURGH, THE	4200 5TH AVE	PITTSBURGH	PA	15260	ALLEGHENY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/17/2021	NEW	$394,375
														Subtotal = $394,375

Grand Total All Awards = $1,535,200

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Adiponectin on cerebrovascular regulation in vascular cognitive impairment and dementia (VCID)

Award Number: R01NS124673

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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