# The Neurodevelopmental Consequences of Genomic Stress

> **NIH NIH F31** · UNIVERSITY OF VIRGINIA · 2020 · $50,520

## Abstract

ABSTRACT:
 The abnormal accumulation of DNA damage in neurons is a shared pathological feature among
neurodegenerative diseases (Alzheimer's disease, Parkinson's disease) and it is also correlated with normal
aging. Transgenic mouse models further demonstrate a specific requirement for DNA repair during
neurogenesis. It is also known that genomic stress, arising from ongoing transcription and metabolic byproducts,
plays a role in aging because it contributes to the accumulation of DNA damage. Previously, studying aging in
the human brain has been incredibly challenging; post-mortem tissue is difficult to acquire and is not amenable
to longitudinal studies. Furthermore, studies of aging have typically looked at model organisms later in life,
meaning that few have assessed how stress exposure impacts the development of the brain and how that
ultimately affects the aging process.
 With the development of human-induced pluripotent stem cells (hiPSCs), we now have an in vitro model
of human neurodevelopment that provides a tool to study models of normal and pathological neurodevelopment.
The goal of this study is to determine how genomic stress and subsequent DNA damage alters the diversity
among hiPSC-derived neural progenitor cells (NPCs) and their progeny. Aim one seeks to determine how NPCs
are resistant to replicative stress and whether this resistance is unique to NPCs compared to isogenic fibroblasts,
astrocytes, and neurons. Multispectral imaging flow cytometry, immunoblotting, and cell cycle analysis will all be
used to elucidate the mechanisms of resistance by investigating DNA damage repair proteins. This aim is
founded on preliminary data indicating that NPCs are resistant to replication stress and particularly susceptible
to transcription associated genomic stress; showing an increase in DNA damage, cell cycle arrest, and DNA
damage signaling activation. Aim two seeks to determine if genomic stress promotes neuroinflammatory
phenotypes through single cell RNA-seq and the human Luminex assay. hiPSC-based neurogenesis provides a
human model system to understand genomic stress related mechanisms in aging and neurodegeneration. This
study will define how neurodevelopmental stress may predispose subsets of neurons for later neurodegeneration
through neuroinflammatory phenotypes, and ultimately lead to consequent studies focused on protecting NPCs
and their progeny from genomic stress to prevent accelerated aging and neurodegenerative disease.

## Key facts

- **NIH application ID:** 10057207
- **Project number:** 5F31AG062042-02
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Nadine Michel
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $50,520
- **Award type:** 5
- **Project period:** 2019-09-30 → 2021-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10057207

## Citation

> US National Institutes of Health, RePORTER application 10057207, The Neurodevelopmental Consequences of Genomic Stress (5F31AG062042-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10057207. Licensed CC0.

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