# DYRK1a as a therapeutic target to treat myocardial infarction

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $403,750

## Abstract

ABSTRACT
Although outcomes after myocardial infarctions (MIs) have improved, cardiomyocytes (CMs) are lost even with
successful reperfusion. This loss contributes to adverse remodeling, ischemic cardiomyopathy, heart failure,
arrhythmia, and death. Current therapies can only slow or reverse isolated aspects of ischemic heart disease,
and there are no reliable therapies available to replace the cardiac muscle loss to MI. Identifying therapeutic
targets and drugs to protect the myocardium after injury will be groundbreaking, address unmet clinical needs,
and represent new strategies to treat cardiovascular diseases. Our goals are to identify and validate druggable
targets that induce controlled CM cycling and improve heart function after injury. However, two challenges exist:
(1) the identification of candidate pathways to stimulate CM cycling with the intent to improve cardiac function
after injury, and (2) the accurate quantification of CM cycling events in adult myocardium. Therefore, we
conducted investigations to address the two challenges. First, we identified an inhibitor of dual-specificity tyrosine
phosphorylation-regulated kinase 1a (DYRK1a), Harmine, increased CM cycling, and improved ventricular
function after MI. Next, we generated CM-specific DYRK1a knockout mice and observed CM hyperplasia at
baseline and improved LV function after MI, suggesting DYRK1a contributes to CM function. Second, we
designed and validated a unique transgenic mouse (denoted αDKRC) that drives Cre in adult cycling
CMs. αDKRC complements existing technologies such as Mosaic Analysis with Double Markers (MADM);
however, the ability to restrict Cre expression to adult cycling CMs is an advance in the field. We
used αDKRC::DTA mice to express Diphtheria toxin in adult cycling CMs and observed that the loss of
endogenously cycling CMs worsened myocardial function after MI. Since cycling CMs are scarce, the findings
suggest that cycling CMs may contribute to myocardial function beyond the concept of a CM as only a contractile
cell, perhaps by expressing paracrine factors. This potential mechanism suggests that modest increases in
cycling CMs may have a more significant impact on cardiac function after MI because cycling CMs serve
functions beyond the concept of contractility. Based on preliminary data, we hypothesize that the inhibition of
DYRK1a improves myocardial function after MI, in part, through enhanced CM cycling and the cycling CMs exert
their effects via paracrine factors. We will test our hypothesis in the following Aims: (1) The CM-specific ablation
of DYRK1a during development protects LV function after MI through enhanced cell cycling, (2) The post-
developmental ablation of DYRK1a in adult CMs will improve LV function after MI, and (3) Cycling CMs contribute
to LV function after MI by expressing paracrine factors. The proposed investigations will define the potential of
DYRK1a inhibition as a treatment of MI, identify the mechanisms through which DYRK...

## Key facts

- **NIH application ID:** 10274952
- **Project number:** 1R01HL158718-01
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Matthew J Wolf
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $403,750
- **Award type:** 1
- **Project period:** 2021-08-15 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10274952

## Citation

> US National Institutes of Health, RePORTER application 10274952, DYRK1a as a therapeutic target to treat myocardial infarction (1R01HL158718-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10274952. Licensed CC0.

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