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Elucidating the cellular and molecular basis of LYST-mediated TEVG stenosis

Award Number: F31HL176054
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2024
PERIOD OF PERFORMANCE END DATE: 05/04/2025

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Elucidating the cellular and molecular basis of LYST-mediated TEVG stenosis - Elucidating the cellular and molecular basis of LYST-mediated TEVG stenosis ABSTRACT A tissue-engineered vascular graft (TEVG) that resists stenosis and grows with the patient has the potential to transform the surgical management of infants and children requiring congenital heart surgery. However, initial clinical evaluation of TEVG efficacy in children revealed an unexpectedly high incidence of graft stenosis or vessel narrowing. In our pursuit to understand the mechanism underlying stenosis, our lab observed reduced rates of TEVG stenosis in mice carrying a mutation in the lysosomal trafficking regulator gene (LYST), which codes for an immunomodulatory protein important for innate immune cell function. As high macrophage infiltration correlated with high rates of stenosis, we initially expected that macrophages were responsible for causing LYST-mediated stenosis. However, macrophage specific LYST dysfunction did not prevent stenosis in mice. In the foreign body reaction to the TEVG, platelet signaling occurs upstream of macrophages, and a growing body of evidence suggests platelets play a critical role in stenosis. Therefore, we hypothesized that the inflammatory response to the TEVG requires LYST-mediated platelet specific signaling that recruits other immune cells to assist in remodeling the developing thrombus into collagen-rich neotissue that persistently occludes or narrows the vessel. Understanding the initial signals driving LYST-mediated stenosis would allow us to harness the therapeutic potential of LYST modulation to prevent graft complications in human patients. In this proposal, we will i.) assess whether LYST dysfunction in megakaryocytes, the precursor cell for platelet production, will prevent TEVG stenosis in murine models, ii.) determine the contribution of purinergic signaling to TEVG inflammation and remodeling, and iii) characterize the time course of LYST involvement in shaping the TEVG immune microenvironment. Successful completion of these studies will deepen our understanding of the LYST-mediated foreign body response to the TEVG and support the development of next generation TEVGs that resist stenosis.


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 = -$28,109 )
2026	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	000	1	3/31/2026	NEW	-$28,109
2026	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	001	1	5/27/2026	NEW	$0
														Subtotal = -$28,109

Issue Date FY: 2024 ( Subtotal = $44,667 )
2024	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Cardiovascular Diseases Research	000	1	8/16/2024	NEW	$44,667
														Subtotal = $44,667

Grand Total All Awards = $16,558

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Elucidating the cellular and molecular basis of LYST-mediated TEVG stenosis

Award Number: F31HL176054

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2024

PERIOD OF PERFORMANCE END DATE: 05/04/2025

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