# Perinuclear Signaling and Cardiac Hypertrophy

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2022 · $557,238

## Abstract

Stimulation of the b-adrenergic receptor (bAR) during the flight-or-fight response increases contractility through
protein kinase A (PKA)-stimulated Ca2+ fluxes at the sarcoplasmic reticulum (SR). However, chronic stress on
the heart leads to long-term stimulation of the bAR by increased circulating catecholamines, resulting in
pathological remodeling due to Ca2+-mediated gene transcription. These divergent responses to bAR activation
and Ca2+ signaling suggests that multiples pools of bAR-regulated PKA activity exist in the cardiac myocyte. We
suggest that internal bARs at the nuclear envelope activate a PKA-stimulated perinuclear Ca2+ signals that
induce pathological gene transcription without affecting cardiac contractility. Therefore, reagents that can block
nuclear bAR and attenuate perinuclear Ca2+ transients should prevent disease initiation and/or progression
without affecting contractility. Our preliminary data finds that PKA bound to the nuclear envelope located
scaffolding protein muscle A-kinase anchoring protein b (mAKAPb) responds to internal bARs to initiate
perinuclear Ca2+ transients that stimulate pathological gene transcription. The central hypothesis of this proposal
is that targeting mAKAPb signalosomes will modulate nuclear b-AR-mediated PKA and Ca2+ responses that
induce pathological disease, without inhibiting, and in fact, maintaining cardiac contractility. Specific Aim 1:
Stimulation of a nuclear pool of Ca2+ is required for induction of cardiac hypertrophy. In this Aim, we will
buffer the mAKAPb-stimulated perinuclear Ca2+ pool using a specifically localized Ca2+ binging protein in order
to determine the importance of this pool for induction of cardiac hypertrophy in adult rat ventricular myoytes.
Using adeno-associated virus to deliver the mAKAPb-targeted Ca2+ “buffer” to the cardiac myocytes in vivo, we
will determine the effect on pathological remodeling induced by pressure overload and catecholamine infusion.
Importantly, the effect of buffering perinuclear Ca2+ on contractility will be investigated. Specific Aim 2:
Inhibition of mAKAPb-bound PKA blocks induction of cardiac hypertrophy. This Aim will use tools that
selectively modulate only mAKAPb-bound PKA to demonstrate that the associated kinase is both necessary and
sufficient for induction of cardiac hypertrophy in vitro and in vivo, while not regulating contractility. Specific Aim
3: A nuclear bAR receptor is responsible for cardiac hypertrophy. Using pharmacological inhibitors,
mAKAP-targeted nanobodies that inhibit specifically nuclear b-AR activation, and siRNA against specific b-AR
subtypes, we will test the hypothesis that internal, nuclear located bARs are responsible for induction of cardiac
hypertrophy. However, modulating these receptors should not affect contractility. Through these Aims, this
proposal will define a novel signaling compartment orchestrated by mAKAPb that is required for pathological
gene transcription and induction of cardiac disease...

## Key facts

- **NIH application ID:** 10372219
- **Project number:** 5R01HL153835-02
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Kimberly L Dodge-Kafka
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $557,238
- **Award type:** 5
- **Project period:** 2021-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10372219

## Citation

> US National Institutes of Health, RePORTER application 10372219, Perinuclear Signaling and Cardiac Hypertrophy (5R01HL153835-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10372219. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*