# Probing macrophage cell nucleotide sensing and calcium signaling through computation

> **NIH NIH R35** · LOYOLA UNIVERSITY CHICAGO · 2024 · $374,836

## Abstract

While inﬂammation is a natural immune system response that begins the healing process, chronic inﬂam-
mation is tied to many human diseases including cancer, cardiac dysfunction, and sepsis. A key element of
inﬂammatory responses are macrophages, a white blood cell that eliminates pathogens or dying tissues. An
endogenous 'danger signal', adenosine triphosphate (ATP), stimulates Ca-dependent inﬂammatory pathways in
macrophages. While previous research has made great strides in understanding inﬂammation, my lab seeks to
uncover roles of ATP in driving macrophage inﬂammatory responses through multi-scale computational models
we develop. With new models of inﬂammatory responses in macrophages, our lab can predict protein and cell
behavior in integrated, physiological systems to better understand the immune system.
 The current paradigm for ATP-triggered inﬂammation in macrophages is that upregulation of nucleotide-
sensing P2X channels sensitizes inﬂammatory responses, including cytokine and reactive oxygen species (ROS)
release. However, this paradigm does not account for several observations. One, while P2X expression is
increased in inﬂammatory macrophages, these receptors also support phagocytosis and migration in resting
macrophages. How these processes are selectively controlled by P2X subtypes like P2X4 and P2X7 is unresolved.
Two, inﬂammatory macrophages harbor post-translational modiﬁcations (PTMs) of many proteins that sense Ca,
yet little is known about how PTMs impact immune pathways they control. Three, release and degradation of ATP
by pannexins and ectonucleotidases control ATP that activates P2X, yet few studies have evaluated their coupling.
 Our lab is uniquely positioned to extend this paradigm by probing mechanisms underlying these observations
and the largely unstudied coupling of P2X-, ATP-, and Ca-driven inﬂammation. Our lab and assembled collab-
orators will investigate the overall hypothesis via computational modeling and experimental approaches: P2X
channels in macrophages help nucleate chronic inﬂammation via ATP-induced ATP release (autocrinic)
mechanisms that selectively prime Ca-dependent, pro-inﬂammatory signaling pathways. This hypothesis
stems from questions that emerged from our investigations during the initial ESI MIRA award: 1. Does increased
P2X4 and P2X7 expression and the resulting Ca signals they induce in macrophages prolong pro-inﬂammatory
release of cytokines and ROS? 2. Do PTMs like ROS oxidation in the Ca-sensor calmodulin (CaM) attenuate its
activation of pro-inﬂammatory signaling pathways? 3. Do (autocrinic) ATP-induced, ATP release in macrophages
prolong pro-inﬂammatory increases in intracellular Ca?
 Our long-term goal to understand macrophage physiology through computation will be accelerated
by the proposed investigations. Key expected outcomes from this grant period include new mechanisms and
simulation tools for autocrinic, ATP-driven inﬂammatory responses mediated by P2X receptors. Since all
Euk...

## Key facts

- **NIH application ID:** 10834008
- **Project number:** 5R35GM148284-02
- **Recipient organization:** LOYOLA UNIVERSITY CHICAGO
- **Principal Investigator:** Peter Michael Kekenes-Huskey
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $374,836
- **Award type:** 5
- **Project period:** 2023-05-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10834008

## Citation

> US National Institutes of Health, RePORTER application 10834008, Probing macrophage cell nucleotide sensing and calcium signaling through computation (5R35GM148284-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10834008. Licensed CC0.

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