# SOD3 regulation of redox sensitive signaling in pulmonary vascular diseases

> **NIH NIH R35** · UNIVERSITY OF COLORADO DENVER · 2020 · $571,435

## Abstract

The overall mission of this research program is to determine how the antioxidant enzyme, extracellular
superoxide dismutase (EC-SOD or SOD3) regulates redox-sensitive signaling pathways responsible for
inflammation and fibrosis in pulmonary vascular diseases across the age span, and harness this knowledge to
design new and precise therapies. The different research projects are based on three complementary themes.
Theme 1 interrogates the regulation of SOD3 expression, activity and distribution in the healthy and diseased
pulmonary circulation in the mature and immature lung. These studies would include in vitro, and in vivo
studies using animal models, as well as activity translating the work through new human studies. They will
address the multiple levels of SOD3 regulation, including genetic polymorphisms, epigenetic regulation, or
other post-translation SOD3 modifications, that can influence gene expression, enzyme activity, half-life and
localization. Theme 2 evaluates how changes in SOD3 activity or binding properties impact redox sensitive
signaling pathways that are responsible for the development of pulmonary vascular disease, in particular,
inflammation and subsequent vascular remodeling and fibrosis. These experiments utilize a unique series of
SOD3 mouse strains, including a mouse with knock-in of a known human SOD3 polymorphism, to interrogate
how individual changes in SOD3 location or content can influence disease pathogenesis and severity. Based
on the unique extracellular localization of SOD3, studies will test the effects of insufficient SOD3 on matrix
integrity, matrix-cell interactions, cell-cell interactions and communication between extracellular signals and
intracellular cellular responses. Ongoing studies are testing how the loss of vascular SOD3 increases the
susceptibility of two key redox-sensitive targets localized to the extracellular matrix (ECM): activation of latent
TGF-β, which enhances PASMC and fibroblast growth, inflammation and synthetic function, or oxidative
fragmentation of hyaluronan, which binds to macrophage CD44 receptors and activates the NLRP3
inflammasome. Future planned studies will test how altered SOD3 impacts the redox landscape to modulate
innate immunity, cellular metabolism and mitochondrial dysfunction responsible for vascular fibrosis in PH.
Theme 3 translates the findings into new therapeutic strategies to replenish deficient SOD3 to restore redox
homeostasis. This framework is supported by a new initiative, funded by a Dean's Strategic Infrastructure
Research Committee Award for the purchase of an electron paramagnetic resonance spectrometer, to develop
a collaborative and interdisciplinary UCD Redox Biology Shared Resource Facility to advance the study of
Redox Biology. These studies collectively will provide new insight relevant to the mission of the Precision
Medicine Initiative, as they will uncover how individual variables that influence SOD3 impact the development
of inflammation and f...

## Key facts

- **NIH application ID:** 9928489
- **Project number:** 5R35HL139726-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Eva S. Nozik
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $571,435
- **Award type:** 5
- **Project period:** 2018-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928489

## Citation

> US National Institutes of Health, RePORTER application 9928489, SOD3 regulation of redox sensitive signaling in pulmonary vascular diseases (5R35HL139726-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9928489. Licensed CC0.

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