# Role of S-nitrosothiols in Akt1 signaling and pneumonia resolution

> **NIH NIH K08** · DUKE UNIVERSITY · 2020 · $118,157

## Abstract

PROJECT SUMMARY/ABSTRACT
This proposal describes a comprehensive five-year training program designed to foster the development of Dr.
Bryan D. Kraft, M.D. (Principal Investigator) into an independent physician-scientist. Dr. Kraft completed his
residency in Internal Medicine and fellowship in Pulmonary, Allergy, and Critical Care Medicine at Duke
University Medical Center where he is now a Medical Instructor. Dr. Kraft’s long term goal is to develop novel
therapeutic approaches to the resolution of acute lung injury (ALI) in critically-ill patients. Dr. Kraft’s research
focus is mechanisms of lung repair following bacterial pneumonia, a leading cause of death worldwide despite
the use of antibiotics. In pursuit of his goal, Dr. Kraft has worked for four years using murine and nonhuman
primate (NHP) pneumonia models under the mentorship of his sponsor, Dr. Claude Piantadosi, an expert in
ALI and mitochondrial quality control mechanisms. Dr. Piantadosi has a record of successfully mentoring more
than 40 junior investigators. The career development program proposed by Dr. Kraft incorporates laboratory
training, formal didactics, attendance at scientific conferences, and an advisory committee composed of
experts in S-nitrosothiol (SNO) biology and mitochondrial signaling mechanisms. During his Fellowship
training, it became apparent that a critical cellular program for lung repair following ALI is mitochondrial
biogenesis, the generation of new mitochondrial mass. Preliminary studies presented in this proposal indicate
that mitochondrial biogenesis can be activated in lung alveolar type II epithelial (AT2) cells, the progenitor cells
of the alveolar region, by pharmacologically augmenting the levels of total lung SNOs. SNO proteins have
undergone S-nitrosylation, a post-translational modification whereby NO is transferred to the sulfur moieties of
cysteine thiols. Preliminary data indicate that a potential mechanism for these findings is S-nitrosylation (and
therefore inactivation) of the protein phosphatases PTEN and PHLPP that de-phosphorylate (de-activate) Akt1,
a protein kinase activator of the transcriptional network for mitochondrial biogenesis. The central hypotheses of
the proposal are that 1) SNOs activate mitochondrial biogenesis in AT2 cells via phosphatase inhibition leading
to increased Akt1 phosphorylation and activation of key downstream repair genes; and 2) SNO-mediated
induction of mitochondrial biogenesis will accelerate lung repair following bacterial pneumonia. These
hypotheses will be tested with the following Specific Aims: 1) Determine if S-nitrosylation of (a) PTEN
and/or (b) PHLPP activate Akt1 and mitochondrial biogenesis in lung AT2 cells; and 2) Determine if
pharmacologic SNO augmentation can accelerate resolution of ALI following murine S. aureus
pneumonia. This work is expected to yield important insight into why endogenous mechanisms may not be
sufficient to resolve severe pneumonia with ALI as well as novel regulatory ...

## Key facts

- **NIH application ID:** 9842293
- **Project number:** 5K08HL130557-04
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Bryan D. Kraft
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $118,157
- **Award type:** 5
- **Project period:** 2017-01-15 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842293

## Citation

> US National Institutes of Health, RePORTER application 9842293, Role of S-nitrosothiols in Akt1 signaling and pneumonia resolution (5K08HL130557-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9842293. Licensed CC0.

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