# Characterization of Atypical p38 signaling in Acute Lung Injury

> **NIH NIH R03** · UNIVERSITY OF GEORGIA · 2023 · $72,104

## Abstract

Mitogen-activated protein kinase (MAPK) p38 is a critical mediator of vascular disruption/edema and
inflammatory signaling associated with
acute lung injury (ALI), acute respiratory distress syndrome (ARDS).
However, p38 directed therapeutics have failed in the clinic due to the physiologically ubiquitous role of p38
activity in all tissues. Thus, there is an essential need to explore alternative mechanisms that selectively regulate
pathological p38 signaling pathways. An understudied atypical p38 activation pathway has recently been
discovered that selectively regulates pathological signaling induced via a direct p38 interaction with the adaptor
protein TAB1, independent from classical p38 activation by MKK3/6. The role of this underexplored pathway
in pulmonary function has not been investigated, representing a major gap in our molecular knowledge
of ALI/ARDS.
P38 signaling is known to regulate inflammatory cytokine expression, vascular dysfunction, macrophage and
neutrophil activation and recruitment, enhancing the progression of pulmonary damage. Atypical p38 signaling
in the vasculature rapidly induces production of inflammatory cytokine expression and blood vessel leakage, and
macrophage recruitment. The goal of these studies is to understand the physiological impact that atypical MAPK
p38 signaling has in pulmonary vasculature during the initial stages of LPS induced acute lung injury, and its
contribution to pulmonary damage.
 Our central hypothesis
disruption, alveolar damage,
is that atypical p38 activation plays a key role in propagating vascular
and pulmonary inflammatory responses in acute lung injury. From this
hypothesis we propose two specific aims: 1) Characterize the contribution of atypical p38 signaling to pulmonary
edema/vascular dysregulation, 2) Characterize atypical p38 pro-inflammatory responses in ALI. We will also use
an acute lung injury (ALI) model using lipopolysaccharide (LPS) in a systemic TAB1-KI mouse verses wild-type
mouse and a cell-penetrating inhibitor peptide which can block atypical p38 signaling. We predict that blockade
of atypical p38 signaling will significantly reduce pulmonary edema in vivo and establish a critical role in
endothelial barrier dysregulation in vitro and in vivo. Furthermore, we predict that these studies will demonstrate
a clear role for atypical p38 signaling in cytokine expression, leading to activation and recruitment of neutrophils
and macrophages. Critically, these studies will be the first to define the role of atypical p38 signaling in acute
lung injury and provide essential foundational evidence for further more detailed studies into pulmonary atypical
p38 signaling. Furthermore, these studies will demonstrate the future therapeutic potential for selectively
inhibiting atypical p38 signaling in vascular and pulmonary inflammatory diseases.

## Key facts

- **NIH application ID:** 10620302
- **Project number:** 5R03AI171967-02
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Neil J Grimsey
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $72,104
- **Award type:** 5
- **Project period:** 2022-05-10 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620302

## Citation

> US National Institutes of Health, RePORTER application 10620302, Characterization of Atypical p38 signaling in Acute Lung Injury (5R03AI171967-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10620302. Licensed CC0.

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