# Mitigating Acute Lung Injury by Cell-specific Targeting of MTOR

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $589,429

## Abstract

Acute lung Injury (ALI) is a common cause of respiratory failure in critically ill patients. It has an incidence of ~
200,000 cases each year in the United States alone and is associated with an unacceptably high mortality rate
of 25-40% and 3.6 million hospital days in reported cases. Although, our understanding of the mechanisms
relevant to the pathogenesis and the resolution of ALI and Acute Respiratory Distress Syndrome (ARDS) has
increased during the past four decades, all current therapies for ALI/ARDS still rely on supportive care and no
effective therapeutic options are available to improve clinical outcome. Thus, the development of new treatment
strategies for ALI/ARDS that are safe, effective, and based on deeper understanding of the mechanisms involved
in ALI pathogenesis is warranted. This proposal aims to clarify the cell type-specific role of MTOR (mechanistic
[formerly mammalian] target of rapamycin) in ALI and test the utility of simultaneous but differential cell-specific
targeting of MTOR to control ALI. The proposal is based on our published and on-going work that implicates a
cell type-specific role for MTOR in inflammation; it mediates inflammation in epithelial cells whereas it serves to
limit endothelial cell inflammation. Intriguingly, however, the “net effect” of MTOR signaling results in a
proinflammatory phenotype in the lung. The proposal will address the following three inter-related, but
independent, aims. Aim 1 will test the hypothesis that MTOR limits ALI by serving an anti-inflammatory function
in pulmonary endothelium. Studies in this aim will ascertain the role of endothelial MTOR in moderating ALI by
determining the effects of modulating MTOR signaling in pulmonary endothelium on lung inflammation and injury.
Aim 2 will investigate the possibility that MTOR promotes ALI by exerting a proinflammatory function in alveolar
epithelium. Aim 2 studies will determine the role of epithelial MTOR in augmenting ALI by monitoring the effects
of modulating MTOR signaling in alveolar epithelium on lung inflammation and injury. Aim 3 will test the
hypothesis that targeting MTOR simultaneously but differentially in a cell type-specific manner (increasing it in
pulmonary endothelium but decreasing it in alveolar epithelium) will yield a superior protective and therapeutic
benefit against ALI. The proposed studies will be carried out using established mouse models of ALI and will
utilize a very new and exciting approach that uses unique cell-specific DNA nuclear targeting sequences (DTSs)
in the plasmid to direct cell-specific plasmid nuclear uptake and gene (shRNA or cDNA) expression in the desired
cell type. The plasmids will be delivered into the lungs of mice via electroporation, which yields high level of gene
expression without inducing inflammation or any cell damage to the epithelial or endothelial cell layer. The
creative use of cell-specific DTS carrying plasmid and electroporation will provide valuable insight into t...

## Key facts

- **NIH application ID:** 10187645
- **Project number:** 5R01HL148695-02
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** David A Dean
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $589,429
- **Award type:** 5
- **Project period:** 2020-06-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10187645

## Citation

> US National Institutes of Health, RePORTER application 10187645, Mitigating Acute Lung Injury by Cell-specific Targeting of MTOR (5R01HL148695-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10187645. Licensed CC0.

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