# Alternative Protein Isoforms in Ventricular Remodeling

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $388,750

## Abstract

PROJECT SUMMARY
Cardiac hypertrophy and failure involve a rewiring of gene expression through alternative splicing, but it remains
unclear which splicing changes are relevant to disease development, and how splice variants affect protein
function. Although many alternative transcript isoforms have been discovered, not all are translated into
proteins and instead may be degraded via non-sense mediated decay or co-translational protein quality control.
Proteomics methods that can identify and quantitate splice variant proteins empirically and on a large scale
provide essential tools to study how alternative splicing regulates cardiac gene expression. We and others
showed that tissue-specific splice variant proteins may be identified using a combined RNA sequencing and
mass spectrometry approach. Accordingly, our goal here is to examine the mechanisms by which alternative
splicing regulates the genetic program in hypertrophic and failing hearts, by identifying the proteins and
pathways that are coordinately regulated by splicing, the resulting complement of protein isoform species
(`proteoforms') in the heart, and the consequences of proteoform sequences on protein structure and function.
Specifically, we plan to: (1) apply a quantitative RNA-guided proteomics framework to identify key isoform
switches at the transcript and the protein level, with emphasis on the changes in splice factors and RNA-binding
proteins in mouse models of systolic and diastolic dysfunction; (2) combine RNA-guided proteomics and
proteome-wide biophysics approaches, we will interrogate the impact of splice variants on protein structure
and thermal stability, and discover significant isoforms through alternative splicing, intrinsically disordered, and
regulatory post-translational modification modules. We anticipate the successful completion of these aims will
generate new conceptual insights into how alternative splicing regulatory networks reprogram the cardiac
proteome in pathological remodeling and heart failure, and more generally, contribute to methods and concepts
to elucidate the regulation and function of alternative splicing in the heart.

## Key facts

- **NIH application ID:** 10814250
- **Project number:** 5R01HL141278-07
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Maggie Lam
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2018-06-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10814250

## Citation

> US National Institutes of Health, RePORTER application 10814250, Alternative Protein Isoforms in Ventricular Remodeling (5R01HL141278-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10814250. Licensed CC0.

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