# Alternative splicing regulation and glucose metabolism in the heart

> **NIH NIH F32** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $65,310

## Abstract

Project Summary/Abstract
 A feature of heart failure is the global reversion from adult to fetal patterns of metabolism and
misregulation of alternative splicing programs. Furthermore, the physiological significance of thousands
of splice forms has yet to be elucidated. This indicates that there is a considerable need to investigate
the factors that govern alternative splicing decisions and their physiological significance in the heart.
Exon 31 of the clathrin heavy chain (Cltc) pre-mRNA is highly included in the heart and skeletal muscle,
and slightly in brain while it is skipped in other tissues. Thus, two tissue specific Cltc isoforms are
generated differing only in the presence or absence of exon 31. The inclusion of Cltc exon 31 is reduced
in the heart during heart failure conditions. The functional importance of these splice forms is highlighted
by the fact that CRISPR engineered mice expressing only the short Cltc splice form lacking exon 31
are protected from pressure-overload induced hypertrophy and heart failure and have reduced AMPK
phosphorylation, compared to mice expressing both Cltc splice forms. AMPK is an intracellular energy
sensor and its phosphorylation promotes glucose transporter (GLUT) translocation to the plasma
membrane and prevents GLUT endocytosis to promote glucose influx. GLUTs are endocytosed in a
clathrin-dependent manner. Therefore, the main research goals of this proposal are: (i) to identify the
RNA-binding proteins (RBP) that regulate alternative splicing of Cltc pre-mRNA (Aim 1), and (ii) to
determine the impact of Cltc splicing regulation on cardiomyocyte metabolism in basal and heart failure
conditions (Aim 2). Aim 2 will further elucidate the energy substrate utilization of cardiomyocytes
expressing Cltc alternative splice forms in basal and heart failure conditions (Aim 2a) and determine
the impact of Cltc splicing in GLUT dynamics in cardiomyocytes (Aim 2b). Targeting metabolic
pathways, GLUT expression, and AMPK are protective in models of heart failure, therefore data from
this proposal will identify novel targetable proteins and pathways to treat or prevent cardiac hypertrophy
and failure.
 The world-renowned scientific environment of UNC-Chapel Hill and the surrounding `Research
Triangle' area will expose the applicant to experts in the fields of cardiac biology, alternative splicing,
cell biology, RNA biology, and metabolism. Furthermore, the training, scientific mentorship, and
experimental design outlined in this F32 postdoctoral fellowship proposal have been tailored specifically
to the applicant's long-term goal: to build a career focused on the intersection between muscle and
RNA biology, nutrient signaling, and alternative splicing function and regulation.

## Key facts

- **NIH application ID:** 9996323
- **Project number:** 5F32HL149147-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Adam J Black
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,310
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996323

## Citation

> US National Institutes of Health, RePORTER application 9996323, Alternative splicing regulation and glucose metabolism in the heart (5F32HL149147-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9996323. Licensed CC0.

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