# Project-004

> **NIH NIH P01** · UNIVERSITY OF IOWA · 2020 · $182,399

## Abstract

To prevent deadly CoV infections we propose to study the molecular basis of coronavirus-induced
lung edema and its resolution, through the identification of (i) Signaling pathways
resulting in severe lung disease to inform inhibitors as antiviral candidates; and (ii) Virus
virulence genes. Deletion of these genes will lead to attenuated vaccine candidates. Three aims
are proposed: Aim 1. To determine the factors involved in edema induction and resolution
during CoV infection. We have shown that both E and 3a proteins of SARS-CoV, and proteins E
and 5 of MERS-CoV include two sequence domains involved in virulence, one containing a PDZ
binding motif (PBM), and another one encoding ion channel (IC) activity. The binding of the
SARS-CoV E protein PBM to proteins containing the PDZ motif causes Acute Respiratory
Disease Syndrome in infected animals. The importance of the PBM is likely associated with its
ability to bind to more than 400 cellular proteins and, therefore, to regulate many cell signaling
pathways. We will study the whole-proteome interactions between PBMs in MERS-CoV, and
cellular PDZs. This interactome will be the basis for the identification of peptides interfering with
PBM-PDZ binding, using peptide libraries. The mechanism of inflammasome activation by
MERS-CoV proteins with IC activity will be studied. Edema resolution is possible by two
enzymatic activities: epithelial sodium channel activity (ENa+C) and Na+/K+ ATPase that move
Na+ ions from the alveolar fluid into the interstitium promoting water elimination. We showed
that SARS-CoV E protein binds Na+/K+ ATPase and have postulated that this binding reduces
Na+/K+ ATPase activity, leading to lung edema; this will be investigated in this project. Aim 2.
We propose to identify viral and host non-coding RNAs involved in MERS-CoV pathogenesis
and lung inflammation, as potential targets in antiviral and anti-edema strategies. Aim 3. To
develop safe live-attenuated vaccines for MERS-CoV. The construction of MERS-CoVs
defective in propagation, and the generation of attenuated, dissemination competent rMERSCoVs
are proposed. Maximizing biosafety and genetic stability of the vaccine candidates
are main goals of the project.

## Key facts

- **NIH application ID:** 10229091
- **Project number:** 5P01AI060699-14
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Stanley Perlman
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $182,399
- **Award type:** 5
- **Project period:** 2004-07-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10229091

## Citation

> US National Institutes of Health, RePORTER application 10229091, Project-004 (5P01AI060699-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10229091. Licensed CC0.

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