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Venous Malformations (VM): A Murine Mdoel to Identify Therapies to Target Aberrant Venous Development

Award Number: R01HL117952
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/12/2013
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Venous Malformations (VM): A Murine Mdoel to Identify Therapies to Target Aberrant Venous Development - PROJECT SUMMARY/ ABSTRACT: Venous malformations (VM) originate from impaired development of the venous network, resulting in massively dilated and dysfunctional veins. Vascular lesions are usually present at birth, continuing to expand with time and never spontaneously regress. VM result in significant morbidity and pain often leading to serious local and systemic complications. Standard clinical management consists of sclerotherapy and surgical resection. However, because these therapies manage symptoms rather than targeting underlying disease etiology, malformed veins often require repeated interventions. Therefore, novel targeted therapies for VM are of high importance. Gain-of function mutations in the endothelial-specific tyrosine kinase receptor TIE2 have been identified as the leading driver of VM. TIE2 has been shown to regulate both maintenance of vascular quiescence and promotion of angiogenesis, but its role in the vascular lumen expansion has not been explored. Research into the molecular and cellular abnormalities which result from hyperactive TIE2 will provide the necessary groundwork for the development of the targeted molecular treatments for VM. Our results, recently published, show that TIE2 signaling promotes activation of c-ABL (Abelson kinase 1) and that genetic and pharmacological c-ABL targeting significantly reduced vascular lumen size. The mechanisms leading to the pathogenic lumen expansion are still largely unexplored and the role of c-ABL in the pathophysiology of VM and vascular anomalies is unknown. With the identification of novel mediators of the TIE2-c-ABL signaling axis, we can now develop a research program to investigate their role in vascular lumen expansion with the goal of identifying novel targets for VM. To perform these studies, we will utilize our VM xenograft murine models and a recently devised in vitro three- dimensional system to study VM lumen formation and expansion. To advance our understanding of VM, we will employ a rigorous approach based on the complementary use of the well-established HUVEC-TIE2-L914F cell line, VM patient derived EC and patient tissue to confirm the significance of our findings for the pathophysiology of VM. Additionally, our studies on VM will provide cellular and mechanistic insights to advance our understanding of pathological and physiological vessel formation and size maintenance.


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 = $0 )
2026	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	10	12/17/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $636,000 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	10	2/28/2025	NON-COMPETING CONTINUATION	$572,401
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	001	10	8/5/2025	NON-COMPETING CONTINUATION	$63,599
														Subtotal = $636,000

Issue Date FY: 2024 ( Subtotal = $623,281 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	9	1/19/2024	NON-COMPETING CONTINUATION	$572,401
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	001	9	6/22/2024	NON-COMPETING CONTINUATION	$50,880
														Subtotal = $623,281

Issue Date FY: 2023 ( Subtotal = $636,000 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	8	3/13/2023	NON-COMPETING CONTINUATION	$636,000
														Subtotal = $636,000

Issue Date FY: 2022 ( Subtotal = $636,000 )
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	7	2/8/2022	NON-COMPETING CONTINUATION	$572,398
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	001	7	5/31/2022	NON-COMPETING CONTINUATION	$63,602
														Subtotal = $636,000

Issue Date FY: 2021 ( Subtotal = $636,000 )
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	6	2/5/2021	COMPETING CONTINUATION	$572,400
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	001	6	2/25/2021	COMPETING CONTINUATION	$0
2021	2021	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	002	6	6/23/2021	COMPETING CONTINUATION	$63,600
														Subtotal = $636,000

Issue Date FY: 2019 ( Subtotal = -$1,096 )
2019	2017	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	5	6/24/2019	NON-COMPETING CONTINUATION	-$1,096
														Subtotal = -$1,096

Issue Date FY: 2017 ( Subtotal = $351,000 )
2017	2017	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	5	4/25/2017	NON-COMPETING CONTINUATION	$351,000
														Subtotal = $351,000

Issue Date FY: 2016 ( Subtotal = $351,000 )
2016	2016	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	4	5/1/2016	NON-COMPETING CONTINUATION	$351,000
														Subtotal = $351,000

Issue Date FY: 2015 ( Subtotal = $345,736 )
2015	2015	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	3	4/20/2015	NON-COMPETING CONTINUATION	$345,736
														Subtotal = $345,736

Issue Date FY: 2014 ( Subtotal = $343,980 )
2014	2014	CHILDREN`S HOSPITAL MEDICAL CENTER	3333 BURNET AVENUE	CINCINNATI	OH	45229	HAMILTON	USA	Cardiovascular Diseases Research	000	2	8/7/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$343,980
														Subtotal = $343,980

Issue Date FY: 2013 ( Subtotal = $374,850 )
2013	2013	CHILDREN'S HOSPITAL CORPORATION	300 LONGWOOD AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	6/12/2013	NEW	$374,850
														Subtotal = $374,850

Grand Total All Awards = $4,932,751

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Venous Malformations (VM): A Murine Mdoel to Identify Therapies to Target Aberrant Venous Development

Award Number: R01HL117952

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/12/2013

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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