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miR regulation of the neurovasculature function in health and disease

Award Number: R01NS107344
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: 08/01/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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miR regulation of the neurovasculature function in health and disease - PROJECT SUMMARY The blood-brain barrier (BBB) is crucial for the health of the brain and is often compromised in neurological diseases such as ischemic stroke. Reperfusion injury following ischemic stroke, due to a neurovascular barrier that is damaged after recanalization of an occluded vessel, is a major risk factor that expands brain damage and needs to be addressed therapeutically. Induced pluripotent stem cell (iPSC)-derived BECs can be used to explore novel mechanisms to enhance angiogenic potential and maintain robust CNS barrier properties promoting functional recovery after disease. This project investigates the mechanisms by which anti-miR-23b enhances the angiogenic and barrier properties of human BECs, and how it augments their ability to repair damaged blood vessels, both in vitro and following ischemia/stroke in vivo. We have found that anti-miR-23b promotes expression and proper localization of TJ proteins and induces formation of a paracellular endothelial barrier, through an anti-miR lentiviral screen in BECs. We have successfully differentiated human iPSCs into BECs exhibiting improved BBB properties, by introducing anti-miR-23b during differentiation. We will test the hypothesis that anti-miR-23b enhances the angiogenic potential and barrier properties of iPSC-derived BECs and promotes repair of the damaged endothelium in vitro and after ischemia and stroke in vivo. We will first examine the mechanisms by which anti-miR-23b enhances the angiogenic potential and structural barrier properties of human BECs, by regulating a network of cellular factors important in EC function. We will validate miR-23b targets, identified by miR-23b RIP sequence analysis, and determine whether miR-23b regulates these mRNA targets directly or indirectly. We will test if the anti-miR-23b-mediated augmentation of angiogenic potential and endothelial barrier function are dependent on increased miR-23b target protein expression. We will then characterize the effects of anti-miR-23b on iPSC-derived BECs in vitro with respect to angiogenesis and paracellular or transcellular barrier properties, using BECs cultured alone or in combination with human pericytes and/or astrocytes. Moreover, we will test if anti-miR-23b expression is sufficient to rescue BBB deficits produced in vitro under oxygen and glucose deprivation conditions. Finally, we will determine if anti- miR-23b overexpression in vivo in CNS blood vessels, using a viral delivery method, enhances BBB repair and reduces stroke volume, tissue injury, immune cell infiltration and neurological deficits in the transient middle cerebral artery occlusion mouse model for ischemic stroke. These experiments will provide both in vitro and in vivo proof-of-concept for using anti-miR-23b to generate BECs with robust barrier properties, which may have the capacity to repair damaged blood vessels following ischemic stroke. We predict that novel strategies to repair BBB injury following stroke will translate to other neurological disorders with BBB dysfunction, such as multiple sclerosis (MS).


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: 2021 ( Subtotal = $472,986 )
2021	2021	SCINTILLON INSTITUTE,THE	6868 NANCY RIDGE DR	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/16/2021	NON-COMPETING CONTINUATION	$472,986
														Subtotal = $472,986

Issue Date FY: 2020 ( Subtotal = $479,535 )
2020	2020	SCINTILLON INSTITUTE,THE	6868 NANCY RIDGE DR	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	8/21/2020	NON-COMPETING CONTINUATION	$0
2020	2020	SCINTILLON INSTITUTE,THE	6868 NANCY RIDGE DR	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	8/12/2020	NON-COMPETING CONTINUATION	$474,759
2020	2019	SCINTILLON INSTITUTE,THE	6868 NANCY RIDGE DR	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	006	3	9/26/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$173,097
2020	2019	SCINTILLON INSTITUTE,THE	6868 NANCY RIDGE DR	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	3	8/21/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$4,776
2020	2019	SCINTILLON INSTITUTE,THE	6868 NANCY RIDGE DR	SAN DIEGO	CA	92121	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/2/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$376,820
2020	2019	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	4/2/2020	NON-COMPETING CONTINUATION	-$376,820
2020	2018	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	1	9/26/2020	NEW	-$173,097
														Subtotal = $479,535

Issue Date FY: 2019 ( Subtotal = $376,820 )
2019	2019	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	4/23/2019	NON-COMPETING CONTINUATION	$376,820
														Subtotal = $376,820

Issue Date FY: 2018 ( Subtotal = $384,072 )
2018	2018	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	7/13/2018	NEW	$384,072
														Subtotal = $384,072

Grand Total All Awards = $1,713,413

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miR regulation of the neurovasculature function in health and disease

Award Number: R01NS107344

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: 08/01/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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