# Tackling the MARCKS-PIP3 Circuit to Attenuate Chronic Pulmonary Fibrosis

> **NIH NIH R43** · EFFECTORBIO, INC. · 2021 · $347,749

## Abstract

Project Summary
Lung fibrosis is an important step of normal lung injury-repair process. However, uncontrolled injury and repair,
and excessive deposition of collagen in the lung parenchyma is the pathological hallmark of chronic pulmonary
fibrosis, such as idiopathic pulmonary fibrosis (IPF). The disease exhibits a median survival time of only 3 to 5
years from the time of diagnosis. Currently, there is no suitable drug for the treatment, except two drugs:
Nintedanib and Pirfenidone, approved by FDA. However, adverse and off-target effects, and failure to
demonstrate increased longevity in treated patients indicate the urgent need for new and better therapeutic
agent(s) to treat this devastating disease. Epithelial-mesenchymal (EM) and fibroblast-myofibroblast (FM)
transitions have been implicated in the initiation and the progression of fibrotic lung pathogenesis. The EM and
FM transition phenomena, important pathogenic events associated with cancer malignancy, are primordially and
mainly mediated by receptor-mediated tyrosine kinase (RTK) and PI3K-AKT signaling pathways. We have shown
before the elevation of phospho-MARCKS in lung cancer tissues/cells associated with EM transition and the use
of a peptide inhibitor, MPS (MARCKS PSD/ED Sequence), to suppress EM transition and lung cancer
malignancy through tackling the aberrant MARCKS-PIP3 circuit associated with cancer pathogenesis. The
elevated phospho-MARCKS phenomenon is also seen in tissue sections and isolated fibroblasts derived from
IPF lungs, but not seen in any normal, non-fiberotic ones. Our recent publication had shown the therapeutic
potential of MPS peptide in the suppression of the fibrotic lesions in bleomycin-induced fibrotic mouse lungs. In
vitro, MPS tackles the aberrant MARCKS-PIP3 circuit to suppress MARCKS phosphorylation and also selectively
inhibits the EM/FM transition and myofibroblast fibrogenesis, as well as the alteration of M1/M2 macrophage
polarization. The selectivity occurs only on IPF-derived fibroblasts and activated macrophage, but not on the
normal and inactivated monocytes. Through peptide optimization, we have developed further a stable, more
biosafe, and high potency of a novel MPS-derived peptide, MPS-6413DTM. Initial studies have shown the efficacy
of this peptide on the suppression of bleomycin-induced lung fibrotic lesions and deceased in mice, but not on
the control ones. We hypothesize that MPS-6413D is a potent anti-fibrotic lung drug on the inhibition of fibrogenic
progression of chronic lung fibrosis through tackling the MARCKS-PIP3 circuit. To test this hypothesis and the
therapeutic potential of this peptide, two aims are proposed. Aim 1 is to determine further the therapeutic effects
of MPS-6413D peptide on bleomycin induced lung fibrotic lesions in aged 32-week old (equivalent to 42 years
old human) mice. The therapeutic potency will be determined on the inhibition of the expression of profibrogenic
marker proteins and their RNA, and the inhi...

## Key facts

- **NIH application ID:** 10152291
- **Project number:** 1R43HL156578-01
- **Recipient organization:** EFFECTORBIO, INC.
- **Principal Investigator:** Reen Wu
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $347,749
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10152291

## Citation

> US National Institutes of Health, RePORTER application 10152291, Tackling the MARCKS-PIP3 Circuit to Attenuate Chronic Pulmonary Fibrosis (1R43HL156578-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10152291. Licensed CC0.

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