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Uncover the Pathogenesis of Brain Arteriovenous Malformation

Award Number: R01NS027713
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

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PROJECT ABSTRACT: Patients with brain arteriovenous malformation (bAVM) are at risk of intracranial hemorrhage (ICH). Overall, bAVM account for 25% of hemorrhagic strokes in adults <50 years of age. The treatment of unruptured lesions has become controversial, because the natural history of these patients may be less morbid than invasive therapies. The mechanism of bAVM formation is not fully understood. There are no specific medical therapies to treat bAVMs. We are among a few groups that have mouse models with bAVM in the brain parenchyma. Using these model, we have identified key factors that are crucial for bAVM formation and progression. We found that the presence of angiogenesis and gene mutation in endothelial cells are essential for bAVM formation. Inflammation may promote bAVM progression. We have also found that bAVM vessels have less mural cell coverage, which is associated with vessel leakage and hemorrhage in mouse bAVMs and in human sporadic bAVMs. Reduction of platelet derived growth factor B (PDGFB) expression in mutant endothelial cells (ECs) might be responsible to the reduction of mural cell coverage. We showed that inhibition of vascular endothelial growth factor (VEGF) signaling through bevacizumab (an anti-VEGF antibody) treatment or intravenous injection of an adeno-associated viral vector (AAV) expressing soluble FMS-related tyrosine kinase 1 (sFLT1) containing the extracellular domain of VEGF receptor 1 inhibits bAVM formation and progression. Increase pericyte coverage by thalidomide treatment reduced the number of abnormal vessels and micro-hemorrhage. The most interesting finding is that homozygous mutation of Alk1 or Eng in a portion of somatic ECs or in bone marrow-derived EC alone is sufficient to trigger de novo bAVM phenotype in the presence of angiogenic stimulation in adult mice. Coincidently, recent studies conducted by others shown that sporadic bAVM and extra-neural AVM harbor somatic mutations in a small number of ECs. It is not clear how a few mutant ECs can cause bAVM formation. In this proposal, we will test our hypothesis that mutant ECs cause bAVM formation and progression through stimulating excessive angiogenesis (Aim 1), impairing pericyte function (Aim 2) and induction of inflammation (Aim 3). In Aim 1, we will show that mutant ECs undergo clonal expansion and release angiogenic factors to stimulate the proliferation of adjacent normal ECs. In Aim 2, we will show that mutant EC impair pericyte function through reduction of PDGFB mediated ANG1, TGFb1 and PDGFRb expression in pericytes. In Aim 3, we will show that mutant EC drives microglia activation, macrophage and lymphocyte infiltration through induction of EC-inflammation. The overarching goal of this project is to identify new therapeutic targets.


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: 2023 ( Subtotal = $504,836 )
2023	2023	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	32	1/4/2023	NON-COMPETING CONTINUATION	$454,353
2023	2023	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	001	32	1/31/2023	NON-COMPETING CONTINUATION	$50,483
														Subtotal = $504,836

Issue Date FY: 2022 ( Subtotal = $523,483 )
2022	2022	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	001	31	3/22/2022	NON-COMPETING CONTINUATION	$52,351
2022	2022	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	31	2/8/2022	NON-COMPETING CONTINUATION	$471,132
														Subtotal = $523,483

Issue Date FY: 2021 ( Subtotal = $537,419 )
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	001	30	1/7/2021	NON-COMPETING CONTINUATION	$53,742
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	30	11/25/2020	NON-COMPETING CONTINUATION	$483,677
														Subtotal = $537,419

Issue Date FY: 2020 ( Subtotal = $525,423 )
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	001	29	2/7/2020	NON-COMPETING CONTINUATION	$52,543
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	29	1/10/2020	NON-COMPETING CONTINUATION	$472,880
														Subtotal = $525,423

Issue Date FY: 2019 ( Subtotal = $487,576 )
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	002	28	4/23/2019	COMPETING CONTINUATION	$109,755
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	28	12/5/2018	COMPETING CONTINUATION	$487,576
2019	2018	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	001	27	4/23/2019	NON-COMPETING CONTINUATION	-$109,755
														Subtotal = $487,576

Issue Date FY: 2018 ( Subtotal = $313,082 )
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	27	4/24/2018	NON-COMPETING CONTINUATION	$31,308
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	27	12/18/2017	NON-COMPETING CONTINUATION	$281,774
														Subtotal = $313,082

Issue Date FY: 2017 ( Subtotal = $313,082 )
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	26	12/23/2016	NON-COMPETING CONTINUATION	$281,775
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	001	26	5/25/2017	NON-COMPETING CONTINUATION	$31,307
														Subtotal = $313,082

Issue Date FY: 2016 ( Subtotal = $313,082 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	25	1/27/2016	NON-COMPETING CONTINUATION	$31,307
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	25	12/10/2015	NON-COMPETING CONTINUATION	$281,775
														Subtotal = $313,082

Issue Date FY: 2015 ( Subtotal = $312,588 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	24	1/9/2015	NON-COMPETING CONTINUATION	$31,259
2015	2015	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	24	11/14/2014	NON-COMPETING CONTINUATION	$281,329
														Subtotal = $312,588

Issue Date FY: 2014 ( Subtotal = $311,106 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	23	12/13/2013	COMPETING CONTINUATION	$311,106
														Subtotal = $311,106

Issue Date FY: 2013 ( Subtotal = $319,617 )
2013	2013	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	22	5/16/2013	NON-COMPETING CONTINUATION	$21,528
2013	2013	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	22	12/19/2012	NON-COMPETING CONTINUATION	$298,089
														Subtotal = $319,617

Issue Date FY: 2012 ( Subtotal = $331,209 )
2012	2012	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	21	1/30/2012	NON-COMPETING CONTINUATION	$331,209
														Subtotal = $331,209

Issue Date FY: 2011 ( Subtotal = $331,209 )
2011	2011	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	1/4/2011	NON-COMPETING CONTINUATION	$304,172
2011	2011	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	20	5/30/2011	NON-COMPETING CONTINUATION	$27,037
														Subtotal = $331,209

Issue Date FY: 2010 ( Subtotal = $334,590 )
2010	2010	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	12/18/2009	NON-COMPETING CONTINUATION	$304,172
2010	2010	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	19	1/20/2010	NON-COMPETING CONTINUATION	$30,418
														Subtotal = $334,590

Issue Date FY: 2009 ( Subtotal = $337,969 )
2009	2009	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	18	12/22/2008	COMPETING CONTINUATION	$337,969
2009	2008	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	12/25/2008	NON-COMPETING CONTINUATION	$0
														Subtotal = $337,969

Issue Date FY: 2008 ( Subtotal = $318,370 )
2008	2008	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	17	4/14/2008	NON-COMPETING CONTINUATION	$318,370
														Subtotal = $318,370

Issue Date FY: 2007 ( Subtotal = $318,772 )
2007	2007	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	16	5/4/2007	NON-COMPETING CONTINUATION	$318,772
														Subtotal = $318,772

Issue Date FY: 2006 ( Subtotal = $328,695 )
2006	2006	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	4/14/2006	NON-COMPETING CONTINUATION	$328,695
														Subtotal = $328,695

Grand Total All Awards = $9,049,120

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Uncover the Pathogenesis of Brain Arteriovenous Malformation

Award Number: R01NS027713

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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