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Human genetics and molecular mechanisms of Vein of Galen aneurysmal malformation

Award Number: R01NS117609
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: 07/15/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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Human genetics and molecular mechanisms of Vein of Galen aneurysmal malformation - PROJECT SUMMARY The genetic study of severe human congenital cerebrovascular anomalies offers the potential to provide actionable understanding of disease pathobiology. Vein of Galen aneurysmal malformations (VOGMs) are the most common and severe neonatal brain arterio-venous malformation (bAVM). Our limited understanding of VOGM pathogenesis impedes the development of improved diagnostic and therapeutic measures. In our previous funding cycle (R01NS117609), we used whole exome sequencing (WES) to discover that damaging de novo variants (DNVs) and inherited variants cause ~20% of VOGMs in a cohort of 114 probands (Neuron, 2019; Nat Commun, 2023). These included an exome-wide significant burden of transmitted variants in Ephrin receptor-B4 (EphB4) and DNVs in Ras suppressor p120 RasGAP (RASA1), genes previously implicated in capillary malformation-AVM syndrome (CM-AVM). We also found, unexpectedly, that EphB4 and RASA1 physically interact via a single SH2-pTyr interaction (JBC, 2023), allowing our development of an enzymatic assay to assess RASA1 Michaelis-Menten kinetics (PNAS, 2025). Nonetheless, the majority of VOGM cases remain genetically unsolved, and the biochemical mechanisms by which VOGM-associated EphB4-RASA1 variants contribute to pathology remain poorly understood. The objective of this R01 renewal is to address these knowledge gaps, employing an integrated, functional genomics approach to discover, functionally validate, and mechanistically elucidate VOGM-associated variants with genome-wide scale and at atomic-level resolution. Preliminary data support our hypothesis that WES of a larger VOGM cohort, coupled with our new endovascularly-enabled VOGM biopsy technique, will enable discovery of novel VOGM risk genes and variants, including somatic “second-hit” variants, that converge to disrupt the activity of an EphB4-RASA1- regulated Ras signaling network required for normal human cerebral arterio-venous specification. To test this hypothesis, Aim 1 will add new VOGM trios to our already largest-in-the-world cohort via our established international VOGM-seq Consortium and use WES to discover novel pathogenic de novo and transmitted germline variants, as well as somatic variants from endovascularly-biopsied VOGM tissue. Prioritized gene candidates will be validated in our zebrafish cerebrovascular screening platform already optimized for EphB4 and RASA1. Aim 2 will determine the functional impact and molecular mechanism of VOGM variants using biochemical, biophysical, and structural biology techniques. Validation experiments will be performed in lesional VOGM tissue and associated cutaneous vascular malformations. Completion of our aims will increase our understanding of human cerebrovascular development and VOGM pathophysiology. Results could improve disease management and genetic counseling and stimulate the development of targeted therapeutics for VOGMs that may also be relevant for the treatment of other bAVMs.


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: 2026 ( Subtotal = $678,120 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	4/17/2026	COMPETING CONTINUATION	$678,120
2026	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/8/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $678,120

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	8/21/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $532,195 )
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/13/2024	NON-COMPETING CONTINUATION	$532,195
														Subtotal = $532,195

Issue Date FY: 2023 ( Subtotal = $552,967 )
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/2/2023	NON-COMPETING CONTINUATION	$552,967
														Subtotal = $552,967

Issue Date FY: 2022 ( Subtotal = $553,785 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	7/28/2022	NON-COMPETING CONTINUATION	$553,785
2022	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	6/22/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2022	2021	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	11/14/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$160,056
2022	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/14/2021	NEW	-$160,056
														Subtotal = $553,785

Issue Date FY: 2021 ( Subtotal = $475,627 )
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	9/14/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$475,627
2021	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/17/2020	NEW	$0
2021	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	9/14/2021	NEW	$0
														Subtotal = $475,627

Issue Date FY: 2020 ( Subtotal = $475,039 )
2020	2020	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/15/2020	NEW	$475,039
														Subtotal = $475,039

Grand Total All Awards = $3,267,733

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Human genetics and molecular mechanisms of Vein of Galen aneurysmal malformation

Award Number: R01NS117609

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: 07/15/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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