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Protective role of let-7 microRNAs in brain endothelial dysfunction during ischemia/reperfusion injury

Award Number: R01NS101135
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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It has been recognized that blood brain barrier (BBB) dysfunction exists in most neurological diseases, including stroke, multiple sclerosis, Alzheimer's and Parkinson's diseases, brain infections and epilepsy. Inflammation plays a significant role in BBB injury, secondary to pro-inflammatory factors produced in the brain or blood and leukocyte engagement of brain endothelium. Brain microvascular endothelial cells (BMVEC) are active participants and regulators of inflammatory processes at a site of inflammation. Inflammatory responses in brain endothelium involve hundreds of genes whose expression requires fine-tuned regulation. microRNAs (miRNAs) recently emerged as major regulators of gene expression. Very limited information exists about their participation in inflammatory responses caused by ischemia/reperfusion (I/R) events in brain endothelial cells. We propose to investigate the role of miRNAs in brain endothelium using well-established in vitro systems for functional studies of the BBB and imaging of brain microvasculature in an in vivo model of neuroinflammation. Based on our studies of BBB dysfunction during neuroinflammation, we propose that barrier protection is best achieved when the intervening agents possess anti-inflammatory properties and can stabilize tight junctions. Recently we have identified highly modified miRNAs, belonging to the let-7 miRNA family, which are important for endothelial maintenance. let-7 and miR-98 were predicted to target the inflammatory molecules, CCL2, CCL5, IL8 and IP10/CXCL10. Overexpression of let-7 and miR-98 in vitro and in vivo resulted in reduced leukocyte adhesion to and migration across brain endothelium and diminished expression of pro-inflammatory cytokines. In oxygen glucose deprivation (OGD) followed by reperfusion (OGD/R), an in vitro I/R model, overexpression of these miRNAs led to increased BBB tightness, thereby attenuating barrier `leakiness'. Overexpression of these miRNAs resulted in decreased infarct volume and neutrophil infiltration in the brain in tMCAO, an in vivo I/R stroke animal model. In our proposed study, we will test the overexpression or inhibition of selected miRNAs on BBB tightness and leukocyte-endothelial cell engagement (adhesion/migration). Using bioinformatics, we will identify other targets for miRNAs. Next, we will perform miRNA transfection in vivo and monitor how the presence of miRNAs will change leukocyte adhesion/migration in an animal model of stroke. Proposed experiments will provide identification and functional assessment of miRNAs in brain endothelium, and lead to future therapeutic developments for prevention of deleterious effects of ischemia/reperfusion on the brain.


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: 2022 ( Subtotal = $346,719 )
2022	2022	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/19/2021	NON-COMPETING CONTINUATION	$312,047
2022	2022	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/29/2022	NON-COMPETING CONTINUATION	$34,672
														Subtotal = $346,719

Issue Date FY: 2021 ( Subtotal = $346,719 )
2021	2021	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/24/2020	NON-COMPETING CONTINUATION	$312,047
2021	2021	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	1/26/2021	NON-COMPETING CONTINUATION	$34,672
														Subtotal = $346,719

Issue Date FY: 2020 ( Subtotal = $346,719 )
2020	2020	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/21/2019	NON-COMPETING CONTINUATION	$312,047
2020	2020	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/11/2020	NON-COMPETING CONTINUATION	$34,672
														Subtotal = $346,719

Issue Date FY: 2019 ( Subtotal = $346,719 )
2019	2019	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/21/2018	NON-COMPETING CONTINUATION	$346,719
														Subtotal = $346,719

Issue Date FY: 2018 ( Subtotal = $339,284 )
2018	2018	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/16/2017	NEW	$339,284
														Subtotal = $339,284

Grand Total All Awards = $1,726,160

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Protective role of let-7 microRNAs in brain endothelial dysfunction during ischemia/reperfusion injury

Award Number: R01NS101135

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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