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Cerebral Microvascular Signaling and Neurovascular Coupling: An Integrated Approach to Investigate VCID

Award Number: R01NS119971
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Cerebral Microvascular Signaling and Neurovascular Coupling: An Integrated Approach to Investigate VCID - SUMMARY Neuronal activity leads to increases in local cerebral blood flow (CBF) to allow adequate supply of O2 and nutrients to active neurons. This process, termed neurovascular coupling (NVC), is essential for survival and its disruption is associated with cognitive decline and dementia. Despite significant findings, we are still far from reaching a comprehensive understanding of NVC. This prohibits us from a thorough understanding of normal brain function and from identifying critical failures in disease and hinders investigations into the vascular origins of cognitive impairment. The objective of this application is to investigate how K+-mediated local CBF control emerges from the integration of neuronal inputs and autoregulatory feedback. This will be accomplished by pursuing two specific aims: In Aim 1, models of endothelial and smooth muscle cells will be developed and examine K+-mediated electrical signaling in capillaries and arterioles. We propose that the inward rectifying K+ channel acts as bistable, “on-off”, switch to hyperpolarize cell membranes when extracellular K+ increases. Multi- cellular models of microvascular networks will examine communication between capillaries and their feeding arteriole, and the significance of capillary-level NVC for local CBF control. We propose that regenerative signal propagation enables this communication and we will test this hypothesis using modeling and an ex-vivo intact arteriole-capillary preparation. In Aim 2, simulations in a geometrically accurate vascular network will predict macroscopic changes in blood flow following functional activation. We will integrate theory and experiments to analyze channelopathy-like defects, in animal models of cerebral small vessel and Alzheimer's disease. We will test the hypothesis that impaired capillary-arteriole communication and altered myogenic response lead to a NVC deficit and propose optimal strategies for restoring this deficit. The proposed work will provide a paradigm for comprehensive examinations of cerebral blood flow control, for interpreting altered cellular signaling in disease and for elucidating vascular underpinnings in cognitive impairment.


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 = $504,146 )
2025	2025	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	7/11/2025	NON-COMPETING CONTINUATION	$504,146
														Subtotal = $504,146

Issue Date FY: 2024 ( Subtotal = $510,489 )
2024	2024	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/10/2024	NON-COMPETING CONTINUATION	$510,489
														Subtotal = $510,489

Issue Date FY: 2023 ( Subtotal = $518,454 )
2023	2023	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/27/2023	NON-COMPETING CONTINUATION	$518,454
														Subtotal = $518,454

Issue Date FY: 2022 ( Subtotal = $523,896 )
2022	2022	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/11/2022	NON-COMPETING CONTINUATION	$523,896
														Subtotal = $523,896

Issue Date FY: 2021 ( Subtotal = $540,881 )
2021	2021	FLORIDA INTERNATIONAL UNIVERSITY	11200 SW 8TH ST	MIAMI	FL	33199	MIAMI-DADE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/30/2021	NEW	$540,881
														Subtotal = $540,881

Grand Total All Awards = $2,597,866

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Cerebral Microvascular Signaling and Neurovascular Coupling: An Integrated Approach to Investigate VCID

Award Number: R01NS119971

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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