# A Mechanistic Clinical Trial of JAK Inhibition to Prevent Ventilator-induced Diaphragm Dysfunction

> **NIH NIH R01** · STANFORD UNIVERSITY · 2021 · $104,609

## Abstract

Project Summary
 The goals of this project are to carry out first-in-human study of the molecule Smad3 to
begin to establish if it is important in the pathogenesis of ventilator-induced diaphragm dysfunction
(VIDD) in humans, and to use this work to train a promising young investigator to work in
translational research. The project will take advantage of the trial design of the parent R01 – a
clinical trial focused on the role of Jak/Stat in VIDD -- to focus upon an additional potential effector
of VIDD. This project will, it is hoped, provide the basis for further clinical drug development based
upon Smad3 as a therapeutic target in VIDD.
 It is known that MV leads to atrophy and weakness of the diaphragm. Since the diaphragm
is primarily responsible for inspiration, its weakness renders it difficult to separate patients from
the ventilator. The resulting ventilator dependence often leads to a spiral of other ventilator-
associated complications that result in increased morbidity and death. A drug that could be given
at the initiation of MV and prevent weakness of the diaphragm would therefore reduce ventilator
dependence and complications/deaths in intensive care unit (ICU) patients.
 The PI’s lab demonstrated that the inter-related molecules Jak and Stat3 are important in
the etiology of VIDD in animals, and the parent R01 is studying this in humans by measuring VIDD
in subjects randomized to Jak inhibition vs. placebo. However, beyond the Jak/Stat pathway, the
lab has also demonstrated that Smad3 appears central to the evolution of VIDD in animals:
Smad3 inhibition prevents VIDD in rats. Validation of whether and how Smad3 contributes to
human VIDD, by study of human diaphragm biopsies, may provide another therapeutic target:
 We will take 2 small diaphragm biopsies, 6 hours apart, in patients undergoing
esophagectomy, and we will characterize the effects of MV on the activation of Smad3; we will
correlate Smad3 activation with VIDD as measured in single, permeabilized, muscle fibers:
Aim 1) Study the effect of MV on Smad3 activity in timed, MV human diaphragm biopsies.
Aim 2) Study the relationship between Smad3 activity and diaphragm weakness in timed,
 MV human diaphragm biopsy specimens.
 This study will thus characterize the relationship between Smad3 activity and diaphragm
muscle weakness in humans undergoing MV. The trainee will learn and apply the research skills
required for a career in respiratory muscle research at the clinical/laboratory interface. Findings
may solidify a novel molecular target for VIDD and support the development of a Smad3 inhibitor
that could be tested in a future clinical trial.

## Key facts

- **NIH application ID:** 10318505
- **Project number:** 3R01HL148185-03S2
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Leah M Backhus
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $104,609
- **Award type:** 3
- **Project period:** 2019-08-20 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10318505

## Citation

> US National Institutes of Health, RePORTER application 10318505, A Mechanistic Clinical Trial of JAK Inhibition to Prevent Ventilator-induced Diaphragm Dysfunction (3R01HL148185-03S2). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10318505. Licensed CC0.

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