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ETS Transcription Factors as Cardiac Maintenance Regulators: Linking Raf-ERK-Pnt Signaling to Adult Cardiac Hypertrophy

Award Number: F31HL189275
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2027
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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ETS Transcription Factors as Cardiac Maintenance Regulators: Linking Raf-ERK-Pnt Signaling to Adult Cardiac Hypertrophy - PROJECT SUMMARY Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous cardiac disorder characterized by ventricular wall thickening, interstitial fibrosis, and impaired cardiac output, often culminating in heart failure or sudden cardiac death. Among the genetic causes of HCM are pathogenic variants in the RAS/MAPK signaling cascade, a core regulator of cellular growth. Aberrant activation of the Raf–MEK–ERK signaling cascade is a defining feature of RASopathies and drives hypertrophic cardiomyopathy (HCM) in both humans and model systems. ERK phosphorylates and activates ETS transcription factors such as PntP2, suggesting that ETS proteins serve as key transcriptional effectors downstream of MAPK signaling. However, the stage-specific roles of ETS factors in the heart, the requirement for ERK-dependent phosphorylation, and the transcriptional programs activated by ETS in vivo remain unknown. In parallel, calcineurin-dependent activation of CRTC represents a second major hypertrophic signaling axis that remodels metabolic and stress-responsive gene networks, but whether ETS integrates or cooperates with CaN–CRTC signaling to drive cardiac growth has not been investigated. This proposal uses the genetically tractable Drosophila heart, an established model for structural and functional cardiac disease, to define how ERK–ETS signaling remodels the adult myocardium and whether it converges with CaN–CRTC pathways to produce hypertrophy. Aim 1 determines when ETS activation is required during development and adulthood and tests whether ERK-mediated phosphorylation of PntP2 is essential for hypertrophic remodeling. Aim 2 uses single-nucleus RNA sequencing and spatial transcriptomics to identify ETS- dependent cell states and downstream transcriptional modules in cardiomyocytes and pericardial cells. Aim 3 tests whether ETS cooperates with, or functions independently of, the calcineurin–CRTC transcriptional module to drive pathological growth. The studies will define the signaling logic and transcriptional networks that underlie cardiomyocyte hypertrophy, identify novel ETS-regulated effectors, and determine how metabolic and MAPK pathways converge to promote pathological remodeling. This work will establish a mechanistic framework for understanding hypertrophic cardiomyopathy and uncover conserved targets for therapeutic intervention in RASopathies and metabolic heart disease.


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 = $38,314 )
2026	2026	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Cardiovascular Diseases Research	000	1	9/4/2026	NEW	$38,314
														Subtotal = $38,314

Grand Total All Awards = $38,314

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ETS Transcription Factors as Cardiac Maintenance Regulators: Linking Raf-ERK-Pnt Signaling to Adult Cardiac Hypertrophy

Award Number: F31HL189275

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2027

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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