# Akt-mediated phosphorylation of hsp70 regulates mitochondrial localization of SOD2 and oxidative stress in pulmonary artery endothelial cells during postnatal transition

> **NIH NIH K08** · MEDICAL COLLEGE OF WISCONSIN · 2020 · $156,153

## Abstract

ABSTRACT
My goal is to become an independent investigator in disease-oriented research in the newborn with a specific
focus on the regulation of mitochondrial oxidative stress in persistent pulmonary hypertension of the newborn
(PPHN). PPHN affects 2-6/1000 live births and is a common cause of cardiopulmonary failure in the newborn.
Of these infants, >30% fail medical treatment and need invasive support measures (ECMO). Oxidative stress
is strongly implicated in the pathogenesis of PPHN. NADPH oxidases are considered the primary source of
superoxide (O2¯) in the pulmonary endothelium. Mitochondrial oxygen consumption during respiration produc-
es influx of O2¯ in the mitochondria as a byproduct of oxidative phosphorylation. Recent evidence indicates
that reactive oxygen species (ROS) produced by mitochondria induce the activation of NADPH oxidases, lead-
ing to ROS induced ROS formation. However, the regulation of mitochondrial O2¯formation remains unknown.
Identification of the adaptive mechanisms that minimizes mitochondrial O2¯formation during exposure to oxy-
gen at birth may identify additional therapeutic targets in PPHN. I will begin to achieve this goal by engaging in
a Career Development plan that logically allows me to expand my prior skills and build new skills in mouse ge-
netics, analysis of protein-protein interactions and identification of novel signaling pathways pertinent to endo-
thelial biology. This plan integrates didactic training in genetics, biochemistry and free radical biology with
learning of skills from my Mentors and Scientific Advisory Committee at the Medical College of Wisconsin who
combined have expertise in endothelial biology, developmental vascular biology, free radical and mitochondrial
biology. The Mentorship and Career Development plan are integrated with the proposed research objectives to
test the hypothesis that Akt induces a post translational modification of hsp70 and modulates the interactions
of hsp70 with two recently identified proteins namely: an Obg like ATPase-1 (OLA1) that facilitates SOD2 im-
port, and CHIP, which is a chaperone-associated ubiquitin ligase that targets hsp70 for degradation. Phos-
phorylation of hsp70 by Akt promotes the interaction of hsp70 with OLA1 and facilitates the mitochondrial im-
port of SOD2 to reduce free O2¯during postnatal transition. The first aim seeks to determine the contributions
of OLA1 and CHIP to the regulation of mitochondrial redox signaling in PAECs. We will use transgenic mice, in
vitro kinetic assays and cell culture to determine the contributions of OLA1 and CHIP to mitochondrial redox
signaling in PAECs and identify how OLA1 and CHIP mechanistically regulate mitochondrial SOD2 import and
ROS production. The second aim will determine the mechanistic role of PI3K/Akt signaling pathway in regulat-
ing the mitochondrial import of SOD2 and the functional relevance of this mechanism to postnatal adaptation.
The successful completion of the proposed studies...

## Key facts

- **NIH application ID:** 9981796
- **Project number:** 5K08HL133379-05
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** Adeleye J afolayan
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $156,153
- **Award type:** 5
- **Project period:** 2016-09-01 → 2022-01-09

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981796

## Citation

> US National Institutes of Health, RePORTER application 9981796, Akt-mediated phosphorylation of hsp70 regulates mitochondrial localization of SOD2 and oxidative stress in pulmonary artery endothelial cells during postnatal transition (5K08HL133379-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9981796. Licensed CC0.

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