# Defining the role of DHHC3 in cardiac stress signaling

> **NIH NIH F32** · CINCINNATI CHILDRENS HOSP MED CTR · 2020 · $65,708

## Abstract

Project Summary
Heart failure remains a significant contributor to both cardiovascular disease and death and it is predicted to
continue to increase in prevalence. A further understanding of the molecular mechanisms contributing to heart
failure will serve to catalyze development of novel therapeutics to treat this disease. Lipid modification of proteins
plays important roles in both their function and localization. Numerous cardiac signaling molecules require
lipidation modification, including small GTPases and heterotrimeric G-proteins. In fact, the molecular mechanism
of statins in treating cardiac hypertrophy is partially attributed to preventing membrane localization of Rho
GTPases by blocking prenylation. Rho GTPases are also S-palmitoylated but unlike prenylation, S-palmitoylation
is a reversible lipid modification that controls dynamic GTPase association with the plasma membrane and their
activity. S-palmitoylation is executed by the recently discovered family of palmitoyl acyltransferases (PATs),
which contain a conserved zinc finger like aspartate-histidine-histidine-cystine (zDHHC) domain for which the
family of proteins are named. The outlined proposal seeks to elucidate how DHHC proteins underlie cardiac
signal transduction, and more specifically, how the Golgi localized DHHC3 (Godz) protein causes pathology.
Preliminary data from the lab showed that cardiac overexpression of Godz in mice results in congestive heart
failure preceded by enhanced palmitoylation, expression, and activity of RhoGTPase in heart. RhoGTPases
have known roles in cardiac stress signaling underlying pathological hypertrophy. This led us to hypothesize that
Godz represents a novel mediator of stress induced pathological signaling in the heart. Two specific aims are
proposed to examine Godz in cardiac function. Aim 1: Examine mechanisms whereby Godz-mediated
intracellular signaling promotes disease in hearts of transgenic mice. Aim 2: Determine the physiologic relevance
of Godz function in pathological hypertrophy. Together, these studies will substantially increase our knowledge
of palmitoylation dependent signaling pathways in heart which may represent a novel therapeutic target for
treatment of heart disease.

## Key facts

- **NIH application ID:** 10064701
- **Project number:** 1F32HL154387-01
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Tanya A. Baldwin
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $65,708
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10064701

## Citation

> US National Institutes of Health, RePORTER application 10064701, Defining the role of DHHC3 in cardiac stress signaling (1F32HL154387-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10064701. Licensed CC0.

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