# Pivotal Role of Oxidation-specific Epitopes in CVD and NASH.

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $370,629

## Abstract

PROJECT SUMMARY
Project 3. Pivotal Role of Oxidation-specific Epitopes in CVD and NASH
Lipid peroxidation, a central event in atherogenesis and NASH, results in formation of oxidation-specific epitopes
(OSE) such as oxidized phospholipids (OxPL), malondialdehyde (MDA) and complex MDA adducts termed MAA,
which we termed “oxidation-specific-epitopes” (OSE). They are proinflammatory and promote chronic
inflammation. Because OSE are mostly products of non-enzymatic lipid peroxidation, mechanisms to specifically
neutralize them were unavailable until now and their actual roles in vivo in disease states such as atherosclerosis
and NASH are unknown. Project 3 is focused on understanding the role of OSE in both atherosclerosis and
NASH and the common (or unique) mechanisms by which they contribute to these diseases. This is now feasible
based on our recent development of transgenic mice that constitutively express single chain antibodies that
target OxPL--the E06-scFv mice—or target MDA/MAA—the IK17-scFv mice. In recently published and new
preliminary data we demonstrate that targeting OxPL in mice consuming NASH producing diets decreases both
atherosclerosis and NASH. Preliminary studies demonstrate that targeting of MDA/MAA can also reduce the
progression of atherosclerosis and hepatic inflammation in a NASH model.
Patients with NAFLD are at increased risk for CVD, and share common risk factors. However, NAFLD confers
additional risk for CVD above that due to known shared risk factors. This Project will test the hypothesis that
OSE are a previously unrecognized common risk factor. Uniquely, this project will simultaneously focus on the
role of OSE in the pathogenesis of atherosclerosis and NASH and define common (or distinct) mechanisms by
which OSE promote these diseases. Specific Aim 1 will use the E06-scFv transgenic mice to study the Role of
OxPL in Atherosclerosis and Hepatic Steatosis/NASH/Fibrosis in mouse models and determine if targeting OxPL
can simultaneously reduce disease burden in both the artery and liver. We will use the E06-scFv mice to
investigate the specific mechanisms by which neutralization of OxPL impacts atherogenesis and liver disease.
Specific Aim 2 will study the Role of MDA/MAA in Atherosclerosis and Hepatic Steatosis/NASH/ Fibrosis in
mouse models in parallel studies to Aim 1. Specific Aim 3 are Translational Studies of the Role of OSE in CVD
and NAFLD/NASH and will seek to determine if targeting OxPL and/or MDA/MAA can not only prevent
progression of disease but cause regression of existing disease. This will be accomplished using newly
generated transgenic mice that conditionally express the antibodies targeting OSE so that enhanced titers can
be achieved after disease is established. This will allow studies to determine if targeting OSE can be therapeutic
and reduce disease burden. These studies should provide an understanding of novel common risk factors
connecting NASH and atherogenesis. Because an antibody-mediated ap...

## Key facts

- **NIH application ID:** 9936776
- **Project number:** 1P01HL147835-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Joseph L. Witztum
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,629
- **Award type:** 1
- **Project period:** 2020-09-21 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936776

## Citation

> US National Institutes of Health, RePORTER application 9936776, Pivotal Role of Oxidation-specific Epitopes in CVD and NASH. (1P01HL147835-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9936776. Licensed CC0.

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