# Biomechanical control of inflammation by the nuclear membrane

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $404,100

## Abstract

Project Summary
The nuclear envelope compartmentalizes genomic and cytoplasmic activities. It also originates a group of lipid-
derived paracrine signals collectively called eicosanoids. Eicosanoids, such as leukotrienes and prostaglandins,
are essential lipid mediators of leukocyte recruitment to infection and tissue damage. Too little eicosanoid sig-
naling causes infection susceptibility, too much can inflict inflammatory bystander injury onto already damaged
organs, and lead to vicious auto-inflammatory circles, for example, during asthma, Crohn’s disease, ischemia,
and cystic fibrosis. Thus, it is of utmost medical importance to understand and therapeutically control this path-
way. To initiate eicosanoid synthesis, cytosolic phospholipase A2 (cPLA2) attaches to the inner or outer nuclear
membrane where it cleaves arachidonic acid, the common fatty acid precursor of all eicosanoids. For long, cPLA2
was thought to be exclusively regulated by chemical signals, such as calcium ions, and protein phosphorylation,
and the reasons for cPLA2’s nuclear localization remained enigmatic. However, our recent research suggests an
unexpected role for nuclear membrane stretch as novel, key regulator of cPLA2 and the eicosanoid cascade in
zebrafish, and human cells. I hypothesize that nuclear biomechanics control innate immune responses through
stretch-sensitive nuclear membrane interactions of inflammatory enzymes, such as cPLA2, 5-lipoxygenase, and
likely others. We will test this hypothesis with an integrated, multilevel approach that ranges from in vitro recon-
stitution to whole animal experiments. First, we will dissect the mechanism of stretch sensing by cPLA2 and
related enzymes by combining microscopic, biophysical, and biochemical assays on artificial bilayers, isolated
nuclei, and intact cells. Second, we will investigate the cytoskeletal regulation of nuclear membrane mecha-
notransduction in various cell culture models of biomechanical stress, as well as by intravital imaging in a
zebrafish infection model. Our work sets out to establish a novel paradigm of nuclear function and cellular mech-
anosensing that can be targeted for therapeutic benefit in the future.

## Key facts

- **NIH application ID:** 10113645
- **Project number:** 5R01GM127356-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Philipp Michael Niethammer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $404,100
- **Award type:** 5
- **Project period:** 2018-05-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113645

## Citation

> US National Institutes of Health, RePORTER application 10113645, Biomechanical control of inflammation by the nuclear membrane (5R01GM127356-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10113645. Licensed CC0.

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