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Caveolin-1 contributes to the long-term function and structure of the neurovascular unit after juvenile concussion

Award Number: R01NS119605
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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Caveolin-1 contributes to the long-term function and structure of the neurovascular unit after juvenile concussion - Summary Project The majority of traumatic brain injury (TBI) is mild in nature but is known to elicit long-term consequences, including emergence of dementia and accelerated age-related declines. The highest-at-risk group are children whose brains are still undergoing development. This proposal will investigate the short- and long-term, cellular and molecular changes in the brain following juvenile mTBI (jmTBI) with the goal to intelligently develop new therapeutic options. Caveolin-1 (Cav-1) is an abundant structural protein involved in caveolae formation and cell signaling which is expressed in cerebral endothelial cells and in astrocytes, key components of the neurovascular unit (NVU). Recent development of a compound to target the Caveolin Scaffolding Domain (CSD), a complex that compartmentalizes structural proteins (e.g. claudin-5) and signaling molecules (e.g. eNOS), has provided tools to explore the role of Cav-1 in acquired neurological disease. After stroke, we found increased Cav-1 expression and Cav-AP treatment was beneficial for post-injury recovery. However, consensus is lacking whether Cav-1 exhibits beneficial or deleterious actions in other acquired brain disorders, such as jmTBI. Our model of jmTBI exhibits accelerated loss of cognition associated with decreased vascular function over their lifespan. We therefore will test the hypothesis that dysfunction in neurovascular coupling after jmTBI can be prevented by modulation of Cav-1 signaling, blunting accelerated hippocampal and cortical aging. Aim 1 will demonstrate that Cav-1 is critical for maintaining NVU functionality. We examine the role of vascular Cav-1 in male & female jmTBI mice in normal (WT), vascular Cav-1 deficient mice (Cav-1-/-) and in Cav-AP treated mice. We believe that jmTBI mice treated with Cav-AP will exhibit vascular recovery, whereas the loss of Cav-1 will worsen NVU outcomes. In Aim 2 we will examine how Cav- 1 in reactive astrocyte processes influences progression of jmTBI. We will modulate Cav-1 expression directly in astrocytes by injecting AAV-GFAP-Cav-1-shRNA and AAV-GFAP-synCav-1 in control and injured mice and quantify vascular recovery and behavioral outcomes. Increased astrocytic Cav-1 will be associated with improved NVU properties and cognitive outcomes. In Aim 3 we will examine male & female mice over their lifespan and examining if increased Cav-1 blunts accelerated brain aging that we have observed after jmTBI. We will assess behavioral, neuroimaging and histological outcomes. jmTBI mice treated with Cav-AP will exhibit improved outcomes related to enhanced NVU function and integrity. In sum, the proposed research is a critical first step in examining the role of Cav-1 in jmTBI and if therapeutic intervention can lead to enhanced NVU stability and function and thereby moderate accelerated aging.


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 = $389,319 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	4/10/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$253,664
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA AT RIVERSIDE	200 UNIVERSTY OFC BUILDING	RIVERSIDE	CA	92521	RIVERSIDE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	3/21/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$389,319
2025	2023	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/20/2025	NON-COMPETING CONTINUATION	$0
2025	2023	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	4/10/2025	NON-COMPETING CONTINUATION	-$253,664
														Subtotal = $389,319

Issue Date FY: 2023 ( Subtotal = $457,352 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	7/13/2023	NON-COMPETING CONTINUATION	$457,352
														Subtotal = $457,352

Issue Date FY: 2022 ( Subtotal = $448,442 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/22/2022	NON-COMPETING CONTINUATION	$448,442
														Subtotal = $448,442

Issue Date FY: 2021 ( Subtotal = $461,801 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/16/2021	NEW	$461,801
														Subtotal = $461,801

Grand Total All Awards = $1,756,914

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Caveolin-1 contributes to the long-term function and structure of the neurovascular unit after juvenile concussion

Award Number: R01NS119605

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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