# Leveraging Protein Kinase G-1 Nanodomain Control and Molecular Targeting to Enhance its Therapeutic Use Against Myocardial Disease

> **NIH NIH R35** · JOHNS HOPKINS UNIVERSITY · 2021 · $981,748

## Abstract

The goal of this project is to re-invent concepts regarding the regulation, targeting, and 
particularly the translational use of protein kinase G (PKG) activation for the goal of treating 
myocardial disease. PKG is the primary enzyme activated by the second messenger cyclic GMP (cGMP) 
and a prominent regulator of vascular tone. Its role in the cardiomyocyte has been more 
controversial, but growing evidence shows that stimulating PKG provides a potent anti-stress and 
pathophysiological brake, countering pro- hypertrophic/fibrotic signaling, mechano-sensing and 
arrhythmia, and improving diastolic function. New data from our lab now shows it can also 
profoundly impact microRNA formation, protein quality control, and autophagy. Cyclic GMP is 
generated by either a nitric oxide or natriuretic peptide signaling-pathway. While both have long 
been viewed as interchangeable, our recent work shows prominent differences in their role and 
regulation in the cardiomyocyte. They operate in nano-domains regulated by specific phospho- 
diesterases; notably PDE5 and PDE9 that target NO and NP stimulated cGMP, respectively. Thus, how 
one activates PK effectively depends upon the disease condition and thus how cGMP is being 
generated, which PDEs are involved, and even the post-translational state of PKG. For example, 
oxidative stress, which depresses NO-stimulated cGMP also oxidizes PKG, which we showed reduces its 
protective effects while also altering its response to agonists. Estrogen depletion impairs 
NO-stimulated cGMP in females, compromising PKG activation strategies dependent on this pathway. 
This R35 program develops four innovative research programs aimed at ultimately improving our 
therapeutic use of PKG activation: 1) Dissect nano-domain controls, defining protein partners, 
selective PKG kinase targets, their dynamics in varying diseases, and how they can be more 
effectively regulated; 2) Identify how co-morbidities such as obesity, metabolic syndrome, and 
post- menopause limit PKG activation strategies, and develop methods to circumvent them; 3) 
Discover novel signaling by which PKG activation provides benefit, including new roles in 
autophagy, proteosome trafficking, pathological mechanosensing and transcriptional controls; and 4) 
Develop a PKG proteotype using new proteomic methods applied  to human heart biopsies and blood. 
Through this work, we aim to transform concepts of PKG therapy for heart disease, based on its 
biology to derive an effective personalized approach.

## Key facts

- **NIH application ID:** 10104372
- **Project number:** 5R35HL135827-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** David Alan Kass
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $981,748
- **Award type:** 5
- **Project period:** 2017-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104372

## Citation

> US National Institutes of Health, RePORTER application 10104372, Leveraging Protein Kinase G-1 Nanodomain Control and Molecular Targeting to Enhance its Therapeutic Use Against Myocardial Disease (5R35HL135827-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10104372. Licensed CC0.

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