# The roles of PLD and DGK isoforms in PIP2 homeostasis during PLC signaling

> **NIH NIH F31** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $48,974

## Abstract

PROJECT SUMMARY
Increases in phospholipase C (PLC) activity have been associated with diseases such as hypertension, and the
current first-line of antihypertensive drugs all target Ca2+ influx that results from PLC activity. However, about
10% of patients with hypertension show resistant hypertension, where blood pressure remains uncontrolled
despite the use of 3+ different antihypertensive drug classes. There is a significant need to find alternative
modulators of PLC activity that are less susceptible to resistance. The downstream lipid produced by PLC,
phosphatidic acid (PA), can regulate PLC signaling by replenishing PLC’s substrate phosphatidylinositol 4,5-
bisphosphate (PIP2). PA is produced downstream of PLC activity by the diacylglycerol kinases (DGK through
DGK) or phospholipase D enzymes (PLD1 and PLD2). The PA then helps to resynthesize PIP2 through
metabolic pathways and through activation of phosphatidylinositol 4-phosphate 5-kinase (PIP5K). Based on this,
the objective of this proposal is to determine how the various DGK and PLD isozymes contribute to PIP2 levels
and PLC regulation. The rationale of the proposed research is to identify new, druggable, isoform-specific targets
to regulate PLC activity in resistant hypertension. The central hypothesis is that PLC signaling activates a
particular subset of DGK and PLD isozymes that are necessary for PI recycling and PIP5K activity, respectively.
We will test this hypothesis using two specific aims: 1) define the DGK isozymes that function in
phosphatidylinositol recycling and 2) determine the role of the DGK and PLD isozymes in PIP5K activation, PIP2
replenishment and downstream Ca2+ signaling. Our research design includes endogenously-tagging the DGK
and PLD isozymes using a CRISPR/Cas9 approach to see how the different isozymes are activated by PLC
signaling. We will then knockdown the PLC-activated isoforms to see how they affect lipid levels, PIP5K activity,
and Ca2+ influx. The proposed research is significant because it will demonstrate how the specific isoforms of
DGK and PLD regulate PLC activity. This is a critical first step in identifying isoform-specific targets for
antihypertensive drug therapies.

## Key facts

- **NIH application ID:** 10898647
- **Project number:** 5F31HL170755-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Claire Weckerly
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898647

## Citation

> US National Institutes of Health, RePORTER application 10898647, The roles of PLD and DGK isoforms in PIP2 homeostasis during PLC signaling (5F31HL170755-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10898647. Licensed CC0.

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