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Endocardial S1PR1 Internalization Drives Congenital Heart Disease via Notch Signaling Dysregulation

Award Number: K99HL186058
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 05/08/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Endocardial S1PR1 Internalization Drives Congenital Heart Disease via Notch Signaling Dysregulation - Project Summary/Abstract: Congenital heart disease (CHD) affects nearly 1% of live births, yet the molecular mechanisms underlying many forms remain poorly defined. Left ventricular noncompaction (LVNC), characterized by excessive trabeculation and myocardial thinning, is associated with defects in endocardial signaling. Recent data suggest that endocardial G protein-coupled receptor (GPCR) trafficking plays a crucial role in modulating cardiogenesis. My research identifies sphingosine-1-phosphate receptor 1 (S1PR1), a GPCR, as a key regulator of Notch1 signaling during late heart development. I discovered that excessive internalization of S1PR1 reroutes cleaved Notch1 from the nucleus to lysosomal degradation, disrupting Notch signaling and contributing to LVNC pathogenesis. The proposed research will elucidate the spatiotemporal regulation and functional consequences of endocardial S1PR1 internalization using advanced mouse genetics and biochemical tools. Specifically, I will (Aim 1) determine the impact of endocardial-specific S1PR1 gain-of-function on trabecular remodeling and Notch activity; and (Aim 2) evaluate whether targeted pharmacologic inhibition of S1PR1 rescues defective endocardial signaling and cardiac morphology. This K99/R00 project is embedded in a rich and collaborative environment at Boston Children’s Hospital and Harvard Medical School under the mentorship of Dr. Timothy Hla, a pioneer in S1P biology. My Advisory Committee includes leaders in developmental cardiology and vascular biology. During the mentored phase, I will expand my expertise in GPCR signaling, single-cell transcriptomics, and in vivo cardiac phenotyping. I will also receive structured training in grant writing, lab management, and scientific communication. My long-term goal is to become an independent investigator leading a research program on GPCR signaling and endocardial biology in heart development and disease. The K99/R00 award will facilitate my transition to independence and support a research trajectory with direct implications for understanding and treating CHDs.


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 = $144,817 )
2026	2026	CHILDREN'S HOSPITAL CORPORATION, THE	300 LONGWOOD AVE	BOSTON	MA	02115	SUFFOLK	USA	Cardiovascular Diseases Research	000	1	5/12/2026	NEW	$144,817
														Subtotal = $144,817

Grand Total All Awards = $144,817

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Endocardial S1PR1 Internalization Drives Congenital Heart Disease via Notch Signaling Dysregulation

Award Number: K99HL186058

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 05/08/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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