# Differential Proteoform Regulation by Alternative Splicing in Cardiac Aging and Hypertrophy

> **NIH NIH F32** · UNIVERSITY OF COLORADO DENVER · 2020 · $64,926

## Abstract

PROJECT SUMMARY
Alternative splicing is a hallmark of cardiac aging and is also causally implicated in the
development of pathological cardiac hypertrophy, suggesting the differential expression of
isoforms may constitute a major molecular mechanism that drives the onset and progression of
cardiovascular dysfunction and diseases. However, the biological functions of most alternative
splicing events are currently uncertain, with many alternative transcripts thought to be degraded
through nonsense mediated decay pathways. To bridge this knowledge gap, there is a need to
identify how alternative splicing regulates cardiac functions on a proteome scale and evaluate
how alternative protein isoforms function differently from their main canonical forms.
Accordingly, the goal of this proposal is to examine the differential regulation of protein isoforms
in young vs. aged hearts and normal vs. hypertrophic hearts as well as to interrogate the functional
impact of isoforms on the onset and progression of cardiac hypertrophy. My Sponsor Dr. Maggie
Lam’s group recently developed an integrated experimental and computational omics workflow
which uses RNA-seq to guide the proteomics identification of alternative isoforms. Here I will test
the hypothesis that alternative splicing drives cardiac aging and pathology by rewiring the
interactome and localization of sarcomeric and metabolic proteins. To achieve this goal, in Aim 1,
I will combine RNA-seq and high-resolution mass spectrometry to determine protein isoforms that
are differentially expressed in aged heart and diseased heart. In Aim 2, I will use fluorescence
imaging technologies to compare the intracellular localization and interacting partners of
canonical and alternative protein isoforms, and discern whether genetic manipulation of
alternative isoforms can ameliorate pathological responses to hypertrophic stimuli.
The anticipated outcome of this study will be an improved understanding of cardiac alternative
splicing, which may contribute insights into molecular pathways involved in cardiac aging and
pathological hypertrophy. At the same time, the research training plan will provide me with
valuable training opportunities in proteomics and data analysis (with Dr. Lam) and cardiac biology
and mouse models (with Co-Sponsor Dr. Peter Buttrick and Collaborator Dr. Timothy McKinsey),
which will complement my existing expertise in imaging and help me achieve my career goal of
becoming an independent investigator in the field of cardiovascular biology.

## Key facts

- **NIH application ID:** 10000771
- **Project number:** 5F32HL149191-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Yu Han
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $64,926
- **Award type:** 5
- **Project period:** 2019-08-06 → 2022-08-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10000771

## Citation

> US National Institutes of Health, RePORTER application 10000771, Differential Proteoform Regulation by Alternative Splicing in Cardiac Aging and Hypertrophy (5F32HL149191-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10000771. Licensed CC0.

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