Friday, June 20, 2025 6/20/2025

Role of SHE and ABL signaling in vascular tubulogenesis

Award Number: R01HL163161
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Role of SHE and ABL signaling in vascular tubulogenesis - Project Summary Formation of vascular lumen of appropriate size, or tubulogenesis, is one of critical steps during vascular development. Many vascular diseases including venous malformations are associated with malformed or enlarged lumens. However, we still have a limited understanding of molecular events that regulate vascular lumen size. Abelson (Abl) kinase signaling regulates diverse processes during development and disease, including cytoskeletal reorganization required for cell morphogenesis, cell motility, adhesion and polarity. Abl signaling in different cell types can induce activation of Rho GTPases, which are known key regulators of lumen formation. However, the role of Abl signaling in regulating vascular lumen size has not been previously investigated. Src homology 2 domain containing E (She) protein was originally identified as a highly conserved factor, which interacted with Abl kinase. We have previously demonstrated that She is specifically expressed in embryonic vasculature in zebrafish embryos. However, its biological function is still unknown in any organism. Here we obtained preliminary data which argues that She acts as a novel regulator of vascular lumen size. Zebrafish mutant embryos deficient in she function display enlarged vascular lumen within the dorsal aorta. Similarly, human vascular endothelial cells, deficient in SHE function, form enlarged tubes. Our preliminary data further suggest that She functions as a novel regulator of Abl signaling, and argue that ABL signaling and lumen formation are misregulated in human venous malformation (VM), suggesting a potential role for ABL and SHE in human disease. We hypothesize that SHE is a novel adaptor protein which functions in the ABL kinase signaling pathway to restrict lumen size during vascular tubulogenesis. We further hypothesize that SHE overexpression may reduce lumen size in VM leading to a novel therapeutic approach. The following specific aims are proposed: 1) Determine the cellular and molecular mechanisms by which She regulates tubulogenesis; 2) Determine if She restricts lumen size by inhibiting Abl kinase signaling pathway; 3) Determine if She overexpression can reduce lumen size in VM. Zebrafish embryos deficient in she function will be analyzed for cellular and molecular defects in vascular tubulogenesis. Conservation of She function will be tested in human vascular endothelial cells. The role of Abl kinase signaling in tubulogenesis and its interaction with She will be analyzed using chemical inhibitors, genetic mutants and biochemical assays in zebrafish embryos and human cells. The therapeutic potential of SHE to reduce the size of vascular lumen will be analyzed in the cell culture and mouse VM model as well as in primary cells isolated from VM patients. Obtained results will identify the role for SHE and ABL signaling during normal and pathological tubulogenesis, which may lead to the development of novel strategies to treat vascular malformations.


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 = $654,813 )
2025	2025	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	000	3	11/20/2024	NON-COMPETING CONTINUATION	$550,204
2025	2025	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	001	3	11/21/2024	SUPPLEMENT FOR EXPANSION	$104,609
2025	2025	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	002	3	6/12/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $654,813

Issue Date FY: 2024 ( Subtotal = $679,708 )
2024	2024	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	002	2	6/21/2024	NON-COMPETING CONTINUATION	$49,036
2024	2024	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	000	2	11/16/2023	NON-COMPETING CONTINUATION	$551,653
2024	2024	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	001	2	3/1/2024	SUPPLEMENT FOR EXPANSION	$79,019
														Subtotal = $679,708

Issue Date FY: 2023 ( Subtotal = $639,384 )
2023	2023	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	000	1	2/22/2023	NEW	$639,384
														Subtotal = $639,384

Grand Total All Awards = $1,973,905

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Role of SHE and ABL signaling in vascular tubulogenesis

Award Number: R01HL163161

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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