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Vasculature provides the substrate for oligodendrocyte progenitor migration in development and disease

Award Number: R01NS097551
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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PROJECT SUMMARY/ ABSTRACT In demyelinating diseases such as multiple sclerosis (MS) and Periventricular Leukomalacia associated with Cerebral Palsy (CP), myelin sheaths are lost through injury or death of oligodendrocytes (OL). Remyelination by oligodendrocyte precursor cells (OPCs) is considered crucial to recovery, but myelin repair often fails contributing significantly to ongoing neurological dysfunction, axonal loss and disease progression. There are currently no therapies to promote remyelination, and one of the greatest unmet needs is gaining a greater understanding of the obstacles to successful myelin repair. Remyelination can be divided into two critical stages: Firstly (1) recruitment of migrating OPCs into areas of demyelination from surrounding normal appearing white matter followed by (2) their differentiation into mature OL within the lesion. We have recently identified that OPCs migrate during their developmental dispersal around the CNS using vasculature as a physical scaffold for motility (Science 351, 379 (2016)). This requires movement along vessels, but also subsequent detachment from vasculature after migration to allow OPC differentiation. The mechanism of migration of OPCs into remyelinating lesions, critical for successful myelin repair, remains largely unclear. This grant will (1) identify for the first time how OPCs are recruited into remyelinating lesions utilizing vasculature as a physical scaffold for motility. It will (2) demonstrate that failure of OPCs to detach from vasculature appropriately is a pathological finding in human white matter injury. It will identify this inability to detach not only as a mechanism preventing their proper distribution into lesions but also as an obstacle for subsequent OPC differentiation. (3) It will show that OPCs remaining inappropriately attached to vessels interfere with astrocyte-vascular coupling and integrity of the blood brain barrier that may contribute further to lesion pathology.


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	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $346,719 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/17/2021	NON-COMPETING CONTINUATION	$346,719
														Subtotal = $346,719

Issue Date FY: 2020 ( Subtotal = $346,719 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	2/26/2020	NON-COMPETING CONTINUATION	$346,719
														Subtotal = $346,719

Issue Date FY: 2019 ( Subtotal = $346,719 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	2/11/2019	NON-COMPETING CONTINUATION	$346,719
														Subtotal = $346,719

Issue Date FY: 2018 ( Subtotal = $346,719 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/24/2018	NON-COMPETING CONTINUATION	$34,672
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/22/2018	NON-COMPETING CONTINUATION	$312,047
														Subtotal = $346,719

Issue Date FY: 2017 ( Subtotal = $346,719 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	3/15/2017	NEW	$346,719
														Subtotal = $346,719

Grand Total All Awards = $1,733,595

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Vasculature provides the substrate for oligodendrocyte progenitor migration in development and disease

Award Number: R01NS097551

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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