Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Role of SIN3a in the epigenetic regulation of the Bone Morphogenetic Protein Receptor Type 2 in pulmonary arterial hypertension

Award Number: K01HL159038
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2025
AWARD TERMINATION DATE: 06/16/2025

Group Awards By:

View Award Description

Role of SIN3a in the epigenetic regulation of the Bone Morphogenetic Protein Receptor Type 2 in pulmonary arterial hypertension - Project Summary PAH is a fatal disease characterized by the progressive remodeling of the distal pulmonary vascular arteries, resulting in elevated pulmonary vascular resistance and pulmonary artery pressure, which may lead to serious complications, such as right heart failure, and ultimately death. Accumulating evidence indicates that endothelial dysfunction is one of the first triggers in PAH that leads to uncontrolled proliferation of vascular cells, vascular remodeling, and occlusion of the pulmonary blood vessels. One of the most common pathomechanisms in PAH is the alteration of the Bone Morphogenetic Protein Type 2 Receptor (BMPR2) signaling in vascular cells. The loss of BMPR2 function, induced by mutation or a loss of expression, is associated with a severe hemodynamic profile and poor outcomes in PAH patients. Multiple studies point to the pulmonary endothelium as the cell type that is most critically impacted by BMPR2 loss in PAH. However, the molecular mechanisms underlying the regulation of BMPR2 expression and its associated PAH-like phenotype remain largely unknown. Our group has recently shown that SIN3a plays a central role in the DNA and histone methylation of the BMPR2 promoter in pulmonary artery smooth muscle cells and the pathogenesis of PAH. However, the epigenetic and transcriptional mechanisms by which SIN3a regulates the BMPR2 gene in PAEC remain to be elucidated. proposal are to uncover the role of SIN3a in the pulmonary endothelial dysfunction Our objectives in this in PAH, identify the downstream mechanisms underlying the regulation of BMPR2 expression in PAEC, and evaluate the therapeutic effects of modified mRNA encoding SIN3a in animal models of PAH. Our preliminary data showed that SIN3a is significantly downregulated in hPAEC isolated from PAH patients. In vitro, we observed that SIN3a silencing downregulates BMPR2 expression and signaling while potentiating PAEC proliferation and migration. Mechanistically, we discovered a novel molecular pathway by which SIN3a modulates BMPR2 levels in hPAECs. Our data showed that SIN3a overexpression upregulates FOXK2 by repressing Enhancer of Zeste Homolog 2 (EZH2)-mediated histone methylation in the FOXK2 promoter. Ultimately, SIN3a overexpression increases FOXK2 binding to the BMPR2 promoter and upregulates BMPR2 levels in hPAECs. Based upon these findings, we hypothesize that the loss of SIN3a impairs BMPR2 expression in PAEC, triggers endothelial dysfunction and vascular remodeling in PAH. In this proposal, our hypothesis will be tested by pursuing the following three specific aims: Aim 1) To investigate the role of SIN3a in endothelial cell dysfunction and decipher the molecular mechanism underlying the regulation of BMPR2 in PAH-hPAEC. Aim 2) To elucidate the effects of SIN3a deficiency in the onset of PAH in smooth muscle cells and endothelial cells using a dual approach. Aim 3) To evaluate the therapeutic efficacy of SIN3a modRNA in preclinical models of PAH. Defining the regulatory mechanisms underlying the loss of BMPR2 expression in PAH will be of great relevance. Finally, restoring the expression of SIN3a in the lungs using SIN3a modified RNA might be a new promising strategy for treating PAH.


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	2024	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Lung Diseases Research	000	3	1/15/2026	TERMINATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Lung Diseases Research	000	3	6/16/2025	TERMINATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $135,303 )
2024	2024	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Lung Diseases Research	000	3	8/1/2024	NON-COMPETING CONTINUATION	$135,303
														Subtotal = $135,303

Issue Date FY: 2023 ( Subtotal = $135,303 )
2023	2023	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Lung Diseases Research	001	2	8/28/2023	NON-COMPETING CONTINUATION	$135,303
2023	2022	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Lung Diseases Research	000	1	11/9/2022	NEW	$0
														Subtotal = $135,303

Issue Date FY: 2022 ( Subtotal = $135,303 )
2022	2022	NEW YORK MEDICAL COLLEGE	40 SUNSHINE COTTAGE RD	VALHALLA	NY	10595	WESTCHESTER	USA	Lung Diseases Research	000	1	8/29/2022	NEW	$135,303
														Subtotal = $135,303

Grand Total All Awards = $405,909

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Role of SIN3a in the epigenetic regulation of the Bone Morphogenetic Protein Receptor Type 2 in pulmonary arterial hypertension

Award Number: K01HL159038

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2025

AWARD TERMINATION DATE: 06/16/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer