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

Mechanisms and Treatments for Right Ventricular-related Inherited Arrhythmias Using Chamber-specific iPSC Models and Engineered tRNA Therapy

Award Number: R01HL184472
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/17/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2030

Group Awards By:

View Award Description

Mechanisms and Treatments for Right Ventricular-related Inherited Arrhythmias Using Chamber-specific iPSC Models and Engineered tRNA Therapy - ABSTRACT Brugada syndrome (BrS) is a heritable arrhythmogenic disease associated with sudden cardiac death, and de- spite decades of research there are no preventative treatments. Although some BrS patients have pathogenic variants in the SCN5A gene, the genetic and mechanistic cause of BrS for the majority patients remains elusive. The rationale for our project is that extensive clinical studies have identified the epicardial right ventricular outflow track (RVOT) as the site of arrhythmogenesis in BrS, but no robust human in vitro models specifically for right ventricular (RV) and RVOT arrhythmic diseases exist. We have strong preliminary data demonstrating a novel protocol to generate iPSC-derived cardiomyocytes with an RVOT-like phenotype (iPSC-rvotCMs). We will har- ness our long-standing expertise with iPSCs and electrophysiology to fill these knowledge gaps. Furthermore, our published studies developing and testing suppressor tRNAs in heterologous systems and other tissues pro- vide impetus to transform the mechanistic studies of BrS into a testbed for this novel treatment approach for nonsense mutations in SCN5A. Our major objectives are: 1) to discriminate the mechanistic causes of BrS aris- ing from pathogenic SCN5A missense and nonsense mutations as well as genotype negative patients using iPSC-rvotCMs and cardiac tissue chips (CTCs) and 2) test anti-codon engineered tRNAs therapy for nonsense mutation BrS. Our central hypotheses are that BrS CTCs will exhibit reduced and heterogeneous conduction with iPSC-rvotCMs showing genotype-dependent reduction in INa, increase in Ito, and Nav1.5/Cx43 mislocaliza- tion. Secondly, we hypothesize that engineered anti-codon tRNAs will partially rescue nonsense SCN5A variants’ Nav1.5 expression and function. Our hypotheses will be tested in 3 specific aims: 1) Identify the role of hypoxia in generation of iPSC-rvCMs and iPSC-rvotCMs and test for developmental defects in BrS; 2) Develop predictive models of BrS using iPSCs to provide mechanistic insights and therapeutic testbeds; 3) Quantify codon-edited tRNA correction of NaV1.5 expression and off-target effects in PTC-related BrS iPSC-rvotCMs. In Aim 1, hypoxia will be used to promote the differentiation of second heart field progenitors to iPSC-rvCMs and iPSC-rvotCMs. Apoptosis of BrS iPSC-rvotCMs in response to hypoxia, a known trigger for RVOT remodeling during develop- ment, will be evaluated. An AI assistant (SteMy) will be designed to improve the reproducibility of the differenti- ation protocols. For Aim 2 we will advance the CTC model to include iPSC-derived epicardial cells to generate Epi-rvot CTCs to investigate arrhythmia mechanisms for BrS using optical mapping, cellular electrophysiology, immunolabeling, and scRNA-seq transcriptomics. Aim 3 will develop codon edited tRNAs to rescue a range of PTCs identified in BrS patients using iPSC-rvotCMs and measure Nav1.5 expression, INa and conduction velocity in CTCs. This project is innovative in the development of novel protocols to produce human iPSC-rvotCMs, introduction of an AI assistant for stem cell culture, generation of CTCs, and development of anti-codon tRNAs to advance the first disease modifying therapy available for BrS.


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 = $789,587 )
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	000	1	8/19/2026	NEW	$789,587
														Subtotal = $789,587

Grand Total All Awards = $789,587

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Mechanisms and Treatments for Right Ventricular-related Inherited Arrhythmias Using Chamber-specific iPSC Models and Engineered tRNA Therapy

Award Number: R01HL184472

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/17/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2030

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer