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Role of Endothelial K+ Channels in Age-Related Dementia

Award Number: R01AG073230
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Role of Endothelial K+ Channels in Age-Related Dementia - Project Summary/Abstract Cerebrovascular endothelial dysfunction impairs blood flow throughout the brain and is a causative factor of age- related cognitive disorders such as Alzheimer’s disease (AD). Approximately 6.2 million Americans are living with AD, whereby more than 95% of patients are over the age of 65; a demographic that will likely double by 2050. Cerebrovascular endothelium coordinates vasoreactivity of blood vessel networks for delivery of oxygen and nutrients throughout brain tissue in accord with metabolic demand. Using a comprehensive, integrative and longitudinal research approach, we endeavor to delineate and mechanistically clarify how endothelial dysfunction precedes and accompanies progression of age-related dementia in the presence of ApoE Ɛ4 (Aim 1) and how the advancement of AD pathology impacts cerebrovascular endothelial function towards endothelial dysfunction (Aim 2). A central pathway for modulation of blood flow to and throughout the brain, but particularly in the microcirculation, involves vasodilatory signaling pathways defined by the function of endothelial K+ channels [Ca2+-activated (SKCa/IKCa; KCa2.3/KCa3.1) and inward-rectifying (KIR2.x) subtypes]. In particular, our recently published data indicate that there are sex-independent reductions in cerebrovascular endothelial KIR2.x channel function with both advancing age and AD pathology in mouse models. Further, our preliminary data demonstrate that mild removal of membrane cholesterol using methyl β-cyclodextrin selectively restores KIR2.x (vs. SKCa/IKCa) channel function to that of young, healthy conditions or better. Thus, we will test the central hypothesis that impairment in endothelial KIR channel function caused by cellular cholesterol underlies cerebrovascular aging and development of dementia. The Aims utilize an innovative integration of ex vivo (isolated cerebral arteries/arterioles, freshly isolated endothelium), in vivo (cerebral perfusion, hyperemia, behavior), and interventional (lipid regulation, cerebral endothelial KIR2.1 channel overexpression) approaches to comprehensively test this hypothesis. The investigating research team includes experts in the biophysics of endothelial function, vascular aging, cerebrovascular physiology/pathology, and cholesterol modulation of endothelial K+ channels. Animal models entail aging endothelial cell-specific KIR2.1+/- & KIR2.1-/-, ApoE Ɛ2 / Ɛ3 / Ɛ4 targeted replacement and 3xTg-AD vs. respective wild-type mice. In such manner, the Research Strategy will be the first to delineate endothelial dysfunction, caused by changes in cellular cholesterol, as a causative pathway of brain aging and AD while focusing on endothelial KIR2.x channels as a novel therapeutic target for pharmacology and gene therapies. We will pursue fine-tuning of K+ channel activity spanning from molecular approaches to the whole organism; reconciling molecular mechanisms with therapy. The ideal outcome is to find and treat precise transitions between physiology and pathology uniting structural and functional vascular “signatures” with behavioral alterations surrounding progressive phases of age- and AD-related dementia.


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 = $643,744 )
2025	2025	LOMA LINDA UNIVERSITY	11145 ANDERSON ST STE 203	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Aging Research	001	4	7/16/2025	NON-COMPETING CONTINUATION	$52,550
2025	2025	LOMA LINDA UNIVERSITY	11145 ANDERSON ST STE 203	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Aging Research	000	4	5/9/2025	NON-COMPETING CONTINUATION	$591,194
														Subtotal = $643,744

Issue Date FY: 2024 ( Subtotal = $668,159 )
2024	2024	LOMA LINDA UNIVERSITY	11145 ANDERSON ST	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Aging Research	000	3	5/15/2024	NON-COMPETING CONTINUATION	$668,159
														Subtotal = $668,159

Issue Date FY: 2023 ( Subtotal = $681,778 )
2023	2023	LOMA LINDA UNIVERSITY	11060 ANDERSON ST BLDG MAGAN HALL	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Aging Research	000	2	4/19/2023	NON-COMPETING CONTINUATION	$681,778
														Subtotal = $681,778

Issue Date FY: 2022 ( Subtotal = $713,703 )
2022	2022	LOMA LINDA UNIVERSITY	11060 ANDERSON ST BLDG MAGAN HALL	LOMA LINDA	CA	92350	SAN BERNARDINO	USA	Aging Research	000	1	4/18/2022	NEW	$713,703
														Subtotal = $713,703

Grand Total All Awards = $2,707,384

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Role of Endothelial K+ Channels in Age-Related Dementia

Award Number: R01AG073230

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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