Sunday, June 1, 2025 6/1/2025

Investigating the intracellular vesicle-mediated mechanism contributing to cerebral cavernous malformation

Award Number: R01HL157019
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Investigating the intracellular vesicle-mediated mechanism contributing to cerebral cavernous malformation - Cerebral vascular malformations affect 1 in 100 to 200 of the general population with increased risk for stroke, seizures and focal neurological deficits. Patients with inherited autosomal dominant CCM carry loss of function mutations in one of three genes: CCM1, CCM2 and CCM3 (Pdcd10). We have focused on CCM3 (Pdcd10) as both humans and mice with CCM3 loss exhibit more severe phenotype than those with loss of CCM1 or CCM2. Why human CCM lesions are primarily confined to the brain vasculature, despite ubiquitous expression of CCM proteins, remains unclear. We have recently established an inducible Ccm3 deletion using a novel brain EC (BEC)-specific Cre line (Pdcd10BECKO) that promoted CCM lesions in the brain. Importantly, the Pdcd10BECKO mice survive up to 6-12 months, allowing us to visualize vascular lesion formation by live imaging, to define the CCM pathogenesis, and to test therapeutics in adulthood. Our previous work shows that CCM3 suppresses Unc13B-dependent exocytosis-mediated secretion of angiopoietin-2. More recent study indicates that caveolae vesicle and its core protein caveolin-1 (Cav1) are tightly controlled by CCM3, and dramatically increased in the brain microvascular ECs of Ccm3- deficient mice. Since increased caveolae has been associated with increased BBB dysfunction, we hypothesize that CCM3, by controlling intracellular vesicles in brain microvascular ECs, regulates BBB integrity; loss of CCM3 induces abnormal vesicle trafficking, particularly caveolae- mediated transcytosis and protein trafficking, leading to BBB dysfunction and vascular malformation. We propose the following three specific aims and studies: 1) To determine the contribution of caveolae and Cav1-mediated signaling to brain vascular malformations. We will determine if Cav1 genetic defect prevents CCM lesion in Pdcd10BECKO mice, characterize BBB function and caveolae-mediated transcytosis, characterize EC-pericyte association and EC lumen dilation in DKO, and characterize novel gene expression and signaling pathways related to BBB structure and function by single cell RNA-seq (scRNA-seq) analyses; 2) To define the mechanism by which CCM3 regulates Cav1-Tie2 signaling and vascular stabilization. We will perform biochemical and imaging experiments to determine if CCM3-regulated Tie2 is caveolae-specific, determine the role of CCM3-Cav1-Tie2 signaling in regulating EC junction, EC-pericyte association and vascular stabilization by in vitro models; 3) To determine the therapeutic effects of Cav1-Tie2 signaling in CCM disease progression. We will test therapeutic effects of Tie2 inhibitor, genetic deletion of Tie2 on CCM disease, define Tie2-mediated gene expression and signaling pathways by scRNA-seq, and determine the role of Tie2high ECs in CCM lesion formation.


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: 2025 ( Subtotal = $418,750 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	000	5	2/14/2025	NON-COMPETING CONTINUATION	$418,750
														Subtotal = $418,750

Issue Date FY: 2024 ( Subtotal = $418,750 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	000	4	2/16/2024	NON-COMPETING CONTINUATION	$418,750
														Subtotal = $418,750

Issue Date FY: 2023 ( Subtotal = $418,750 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	000	3	2/21/2023	NON-COMPETING CONTINUATION	$418,750
														Subtotal = $418,750

Issue Date FY: 2022 ( Subtotal = $418,750 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	000	2	3/14/2022	NON-COMPETING CONTINUATION	$376,875
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	001	2	6/8/2022	NON-COMPETING CONTINUATION	$41,875
														Subtotal = $418,750

Issue Date FY: 2021 ( Subtotal = $418,750 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	001	1	7/2/2021	NEW	$41,875
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Cardiovascular Diseases Research	000	1	3/15/2021	NEW	$376,875
														Subtotal = $418,750

Grand Total All Awards = $2,093,750

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Investigating the intracellular vesicle-mediated mechanism contributing to cerebral cavernous malformation

Award Number: R01HL157019

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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