# Diacylglycerol kinase in airway smooth muscle functions

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2020 · $499,598

## Abstract

Gq-coupled G protein coupled receptors (GPCR) on airway smooth muscle (ASM) cells are critical
regulators of the airway hyperresponsiveness (AHR) and airway remodeling that occurs with asthma. Gq
signaling in ASM involves activation of phospholipase C that converts phosphoinositol 4,5-bisphosphate (PIP2)
into diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). While IP3 leads to increases in [Ca2+]i,
phosphorylation of MLC20 and ASM contraction, DAG directly activates PKC family members and Ras guanyl
nucleotide-releasing protein. The signaling and functional role of DAG in ASM is largely unknown. DAG is
known to be phosphorylated and further converted into phosphatidic acid (PA) by enzymes known as DAG
kinases (DGK). Both PA and DAG are important lipid mediators that can activate numerous signaling proteins
and therefore, intracellular levels of DAG and PA are tightly regulated. The impetus for the proposed studies is
our preliminary observation that mice lacking  isoform of DGK are protected from ovalbumin-induced AHR in
spite of full complement of airway inflammation. In this proposal we seek to establish the mechanisms by which
DGK regulates ASM contraction and proliferation with the central hypothesis that DGKs play a key role in
regulating ASM contraction (via PIP2-DAG/IP3 axis) and proliferation (via PIP2-DAG/PA axis), and inhibition of
DGK blocks the asthmatic airway response by affecting the contractile (AHR) and proliferative (remodeling)
function of ASM cells. To achieve our research goals, we will employ diverse, state-of-the-art tools such as
targeted lipidomics, fluorescence sensors of PIP2/DAG and genetic/pharmacological inhibition of DGK. We
contend that acute inhibition of DGK results in accumulation of DAG that acts as a negative feedback regulator
and inhibit Gq-PLC signaling in ASM cells. In Aim 1 studies we will discern multiple mechanisms by which DGK
isoforms regulate Gq-coupled GPCR-mediated ASM contraction. Additional preliminary data suggest that PA is
a pro-mitogenic signaling molecule in ASM and DGK inhibition leads to attenuation of ASM growth. Therefore,
Aim 2 studies will establish the molecular and cellular mechanisms by which DGK isoforms regulate ASM cell
proliferation. Finally, to establish the in vivo relevance of DGK inhibition, Aim 3 studies will employ a house
dust mite (HDM)-induced mouse model of asthma and test the effect of DGK inhibition on allergen-induced
AHR and ASM remodeling. DGK inhibition will be achieved either by using smooth muscle specific conditional
deletion of DGK or by treating animals with a pharmacological inhibitor of DGK (R59022). Our success is
favored by the availability of a unique cell-type specific DGK isoform knockout mice, our team’s ability to
creatively apply cutting edge imaging approaches, and the use of multiple complementary approaches to
discern the complex (im)balance of lipid signaling molecules in ASM cells. The findings will not only advance
the basic scien...

## Key facts

- **NIH application ID:** 9898459
- **Project number:** 5R01HL146645-02
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Deepak A Deshpande
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $499,598
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898459

## Citation

> US National Institutes of Health, RePORTER application 9898459, Diacylglycerol kinase in airway smooth muscle functions (5R01HL146645-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898459. Licensed CC0.

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