# Diacylglycerol kinase in airway smooth muscle functions

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2024 · $654,449

## Abstract

Project Summary
 Gq family G protein-coupled receptors (GPCR) and receptor tyrosine kinases (RTKs) on airway smooth
muscle (ASM) and T cell receptors (TCR) on T cells are critical in orchestrating cellular responses leading to
airway hyperresponsiveness (AHR), remodeling and inflammation in asthma. Activation of these receptors
leads to the generation of diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3) by the action of
phospholipase C. DAG, working in synergy with IP3-Ca2+ signaling and directly activating PKC and Ras guanyl
nucleotide-releasing protein, promote ASM contraction and proliferation. However, the independent role of
DAG in ASM functions remains less explored. DAG is phosphorylated and further converted into phosphatidic
acid (PA) by enzymes known as DAG kinases (DGK). Our studies in the last grant cycle demonstrated that
pharmacological and genetic inhibition of DGK inhibits ASM cell contraction and proliferation and attenuates
the development of allergen-induced airway inflammation, features of airway remodeling, and AHR in mice.
The functional effects of DGK inhibition are counter-intuitive as DGK inhibition is expected to enhance DAG-
mediated signaling and promote ASM contraction and proliferation. The functional dichotomy of DGK inhibition
suggests a complex relationship between phospholipid second messengers and the enzymes responsible for
their synthesis (PLC) and degradation (DGK). Indeed, the preliminary data presented in this application
suggest that low-level and transient elevation of DAG negatively regulates Gq-PLC activity. In this proposal, we
aim to uncover the molecular mechanisms by which DGK regulates ASM contraction and proliferation and T
cell-mediated immune response. Our central hypothesis posits that DGK isoforms serve as pivotal regulatory
checkpoints and fine-tune the spatiotemporal phospholipid signaling in ASM cells. Further, the inhibition of
DGK perturbs this delicate equilibrium and attenuates the asthmatic airway response by affecting the
stoichiometry of lipid second messengers responsible for ASM functions. To achieve our goals, we will employ
diverse, state-of-the-art tools such as targeted phosphoproteomics, lipidomics, fluorescence sensors and
genetic/pharmacological inhibition of DGK. In Aim 1 studies, we will discern how DGK inhibition impacts
phospholipid signaling and the activation of effectors involved in ASM contraction. In Aim 2, our studies will
focus on establishing how DGK isoforms regulate DAG kinetics and signaling, which in turn regulate ASM cell
proliferation. Finally, to establish the therapeutic relevance of our findings, Aim 3 studies will test the efficacy of
a newly developed DGK isoform-specific small molecule inhibitor (ASP1570) in mitigating features of allergic
asthma in a murine model. We will also discern the mechanism by which DGK inhibition modulates T cell-
mediated immune response. Collectively, our studies will provide a deeper understanding of the intric...

## Key facts

- **NIH application ID:** 10981181
- **Project number:** 2R01HL146645-05
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Deepak A Deshpande
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $654,449
- **Award type:** 2
- **Project period:** 2019-04-01 → 2025-09-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10981181

## Citation

> US National Institutes of Health, RePORTER application 10981181, Diacylglycerol kinase in airway smooth muscle functions (2R01HL146645-05). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10981181. Licensed CC0.

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