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A vasculo-protective role for beta4 integrin in neuroinflammation

Award Number: R01NS103966
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: 12/01/2018
PERIOD OF PERFORMANCE END DATE: 02/29/2024

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A vasculo-protective role for beta4 integrin in neuroinflammation - PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) is a chronic inflammatory disease characterized by demyelination and degeneration of axons in the central nervous system (CNS). Early in MS and experimental MS (experimental autoimmune encephalomyelitis, EAE) breakdown of the blood-brain barrier (BBB) and angiogenic remodeling initiate and maintain pathogenesis by affording leukocyte infiltration into the CNS. This vascular remodeling, in turn, is strongly influenced by extracellular matrix (ECM) proteins and their endothelial integrin receptors. We hypothesize that one specific integrin, the laminin receptor, plays an important vasculo-protective role during neuroinflammation by promoting BBB integrity and suppressing endothelial inflammation. This hypothesis is supported by several observations. First, laminin is a major component of the vascular basal lamina, and transgenic mice deficient in astrocyte and pericyte laminin show defective BBB integrity. Second, while most blood vessels in the normal brain express only low levels of  integrin, endothelial cells in all vessels strongly upregulate this integrin during inflammation. Third, we have recently found that transgenic mice lacking endothelial  integrin expression (-EC-KO mice) show worse clinical disease and increased neuroinflammation in EAE. Fourth, our in vitro studies of brain endothelial cells suggest that 4 integrin protects both by maintaining vascular integrity (via claudin-5 stabilization) and by reducing vascular activation (via reduced ICAM-1 expression). Taken together, these data suggest that  integrin upregulation may be an inducible protective mechanism that stabilizes the BBB under conditions of stress. Furthermore, we have found that the cholesterol-lowering drug atorvastatin upregulates endothelial  integrin expression in vivo, suggesting that this could provide an effective way to therapeutically manipulate  integrin levels in MS. As part of these studies we will also generate a novel transgenic mouse strain in which  integrin is over-expressed specifically in endothelial cells (-EC-high) and test whether these mice are protected against neuroinflammation. In vitro studies will define which inflammatory mediators induce endothelial 4 integrin expression and examine the mechanisms underlying statin-induction of endothelial integrin. Lastly, we will define the roles of three signaling pathways in mediating  integrin-mediated vasculo- protection: (i) TGF- ALK1-Smad 1/5/8, (ii) MAP kinase, and (iii) myosin light chain (MLC) kinase. Our hypothesis will be tested in three specific aims: (1) define mechanistically how 4 integrin protects against neuroinflammatory disease, (2) demonstrate that upregulation of endothelial 4 integrin protects against EAE and (3) define the intracellularsignaling pathways that mediate the vasculo-protective influence of integrin. The approach is innovative because it will test the novel concept that  integrin promotes BBB integrity and suppresses vascular inflammation during EAE. This research is significant because successful completion of these studies will evaluate endothelial  integrin as a novel MS therapeutic target.


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: 2024 ( Subtotal = $0 )
2024	2022	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT STE 200	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	7/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $420,000 )
2022	2022	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	4/8/2022	NON-COMPETING CONTINUATION	$42,000
2022	2022	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	3525 JOHN HOPKINS CT	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	3/10/2022	NON-COMPETING CONTINUATION	$378,000
														Subtotal = $420,000

Issue Date FY: 2021 ( Subtotal = $420,000 )
2021	2021	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/10/2021	NON-COMPETING CONTINUATION	$420,000
														Subtotal = $420,000

Issue Date FY: 2020 ( Subtotal = $420,000 )
2020	2020	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/31/2020	NON-COMPETING CONTINUATION	$420,000
														Subtotal = $420,000

Issue Date FY: 2019 ( Subtotal = $420,000 )
2019	2019	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	2/6/2019	NON-COMPETING CONTINUATION	$420,000
2019	2018	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	2	4/23/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$30,476
2019	2018	SAN DIEGO BIOMEDICAL RESEARCH INSTITUTE	10865 ROAD TO THE CURE STE 100	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	12/10/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$87,075
2019	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/10/2018	NEW	-$87,075
2019	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	1	4/23/2019	NEW	-$30,476
														Subtotal = $420,000

Issue Date FY: 2018 ( Subtotal = $423,281 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/27/2018	NEW	$423,281
														Subtotal = $423,281

Grand Total All Awards = $2,103,281

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A vasculo-protective role for beta4 integrin in neuroinflammation

Award Number: R01NS103966

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: 12/01/2018

PERIOD OF PERFORMANCE END DATE: 02/29/2024

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