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Fibroblast-derived laminin regulates blood-brain barrier integrity and fibroblast biology in hemorrhagic brain

Award Number: R01NS134134
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: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Fibroblast-derived laminin regulates blood-brain barrier integrity and fibroblast biology in hemorrhagic brain - Project Summary/Abstract The long-term objective of this application is to develop innovative therapies for intracerebral hemorrhage (ICH), which causes high rates of death and disability worldwide. This is consistent with the mission of NINDS. This proposal aims to investigate the biological functions of fibroblast-derived laminin in blood-brain barrier (BBB) repair and fibroblast biology after ICH and explore the underlying molecular mechanisms. In Aim 1, the function of fibroblast-derived laminin in ICH pathogenesis will be investigated in two clinically relevant ICH models using middle-aged transgenic mice with laminin deficiency in fibroblasts. In Aim 2, the function of fibroblast-derived laminin in BBB repair after ICH will be investigated both in vitro and in vitro. First, how loss of fibroblast-derived laminin affects BBB permeability and inflammatory cell infiltration after ICH will be examined (Aim 2A). Next, whether loss of fibroblast-derived laminin exacerbates BBB disruption via paracellular and/or transcellular mechanisms will be investigated (Aim 2B). Third, the receptors that mediate fibroblast-derived laminin’s “BBB-repairing” effect on endothelial cells will be identified using both pharmacological and genetic approaches (Aim 2C). In Aim 3, the function of fibroblast-derived laminin in fibroblast biology and fibrotic scar composition will be investigated. First, fibroblast biology (proliferation/apoptosis/migration), fibroblast morphology, and fibrotic scar components will be examined in vitro and in vivo (Aim 3A). Next, how exactly fibroblast-derived laminin regulates fibroblast biology and fibrotic scar composition will be explored by bulk and/or single-cell RNAseq analysis (Aim 3B). Third, the receptors that mediate these changes in fibroblasts will be identified using both pharmacological and genetic approaches (Aim 3C). Successful completion of this proposal will elucidate novel functions of fibroblast-derived laminin in BBB repair and fibroblast biology after ICH, identify the receptors that mediate these effects on both endothelial cells and fibroblasts, provide new molecular targets with therapeutic potential, and promote the development of innovative and effective treatments for ICH.


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: 2026 ( Subtotal = $493,944 )
2026	2026	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/29/2026	NON-COMPETING CONTINUATION	$493,944
														Subtotal = $493,944

Issue Date FY: 2025 ( Subtotal = $493,944 )
2025	2025	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/5/2025	NON-COMPETING CONTINUATION	$493,944
														Subtotal = $493,944

Issue Date FY: 2024 ( Subtotal = $479,126 )
2024	2024	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	8/2/2024	NON-COMPETING CONTINUATION	$479,126
														Subtotal = $479,126

Issue Date FY: 2023 ( Subtotal = $489,819 )
2023	2023	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/21/2023	NEW	$489,819
														Subtotal = $489,819

Grand Total All Awards = $1,956,833

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Fibroblast-derived laminin regulates blood-brain barrier integrity and fibroblast biology in hemorrhagic brain

Award Number: R01NS134134

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: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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