# Altered Hippocampal Neurogenesis and Cognition via Maneb-mediated Changes in the Thiol Redox Proteome.

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2021 · $380,240

## Abstract

Abstract
The overall goal of this proposal is to elucidate the thiol redox mechanisms that increase xenobiotic toxicity,
alter neurite outgrowth, and enhance neurodegeneration. The thiol redox proteome is the adaptive interface
between the genome and exposome, providing a means to sense, avoid, and defend against oxidants and
other toxicants. Disruption of cellular thiol redox systems, e.g. thiol redox proteome, is a key feature of
oxidative stress, contributing to age-related diseases, including neurodegeneration. Enhanced reactive oxygen
species (ROS) production in a variety of conditions is linked to mitochondrial dysfunction. Thus, genetic factors
or disease processes that cause increased basal levels of stress may result in increased susceptibility of
certain populations to environmental exposures. Our preliminary data indicate that individuals with Down
syndrome (DS) may be sensitive to the toxic effects of xenobiotics due to their enhanced basal levels of stress.
DS is the most common genetic form intellectual disability and the cognitive phenotype can be highly variable.
This variability cannot be completely explained by genetics. Additionally, due to a triplication of the amyloid
precursor protein gene (APP), all DS patients develop Alzheimer's-like pathology. Based upon preliminary data
and published reports, it is hypothesized that environmental exposures contribute to cognitive phenotype
variability via disrupted thiol redox signaling and control due to enhanced basal levels of cellular stress and
mitochondrial dysfunction. Because ER and oxidative stress are fundamental mechanisms of
neurodegeneration, this proposal will investigate the role of redox signaling in the effects of MB on stem cells
derived from DS patients, how these exposures affect neurite outgrowth, and how cognitive function is altered
in a transgenic mouse model of DS. In Specific Aim 1, we will elucidate the mechanisms of enhanced MB
toxicity in DS. Specifically, we will study the roles that oxidative stress, ER stress and mitochondrial
dysfunction play in MB-mediated toxicity in DS. In Specific Aim 2, we will utilize iPS cell-derived neural
progenitor cells and mature neurons from DS patients and euploid controls to evaluate disease- and toxicant-
mediated changes in neurite outgrowth using high-content imaging techniques. Interventions will also be
employed to investigate the impact of oxidative stress and ER stress on neurite outgrowth. Alterations in
neuronal thiol redox proteome will also be determined using isotope-coded affinity tag (ICAT) redox
proteomics. Lastly, in Specific Aim 3 an in vivo mouse model of DS, Dp(16)1Yey/+, will be used to determine
the influence of DS and MB exposure on cognitive function. This aim will also characterize MB-mediated
neurodegeneration of the hippocampus, and elucidates redox sensitive pathways altered in the hippocampus
that impair learning and memory via ICAT redox proteomics. Successful completion of these aims will prov...

## Key facts

- **NIH application ID:** 10113616
- **Project number:** 5R01ES027593-05
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** James R Roede
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $380,240
- **Award type:** 5
- **Project period:** 2017-03-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10113616

## Citation

> US National Institutes of Health, RePORTER application 10113616, Altered Hippocampal Neurogenesis and Cognition via Maneb-mediated Changes in the Thiol Redox Proteome. (5R01ES027593-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10113616. Licensed CC0.

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