# Role of DNA double-strand breaks in neural function and homeostasis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $331,075

## Abstract

PROJECT SUMMARY/ABSTRACT
Aging-associated brain disorders, including cognitive decline, are among the greatest public health challenges.
DNA repair is emerging as a potential regulator of age-related cognitive decline and neurodegeneration, and
may be a powerful potential target for effective therapeutic strategies in the future. The brain may be vulnerable
to genomic alterations due to its network structure, the complexity of its transcriptome, and the low or absent
turnover and long lifespan of neural cell types. This suggests genome maintenance pathways are crucial for
brain health: persistent or incorrectly repaired DNA double-strand breaks (DSBs) could contribute to genomic
alterations, thus promoting age-related cognitive impairment and neurodegenerative disorders. However, the
role of post-developmental, neuronal DSB repair in brain physiology with age has not been addressed. The
broad implication for this fundamental gap in knowledge is that crucial opportunities for development of
therapeutics for treatment and prevention of brain disorders may be missed. This provides a strong rationale for
elucidating the biology of neuronal DSB repair at multiple levels. Thus, our long-term goal is to determine the
extent to which neuronal DNA double-strand break formation and repair impact brain function and brain
disorders. We will elucidate the relationship between neural circuit function and the classical non-homologous
end-joining (C-NHEJ) DNA repair machinery in neurons with age. Moreover, we will elucidate the extent to which
post-developmental, neuronal DSB repair suppresses brain aging phenotypes related to chromatin structure,
genome organization, and gene expression.
The central hypothesis of the proposed project is that DNA double-strand break formation and repair in mature
neurons impacts neural physiology. To test this hypothesis and to advance toward our long-term goal, we
propose the following specific aims: (1) Define consequences of aging and C-NHEJ inactivation in neurons at
the cellular and genomic level; (2) Elucidate impact of aging and C-NHEJ inactivation on the neuronal epigenomic
landscape; and, (3) Determine impact of aging and C-NHEJ repair on circuit-level neuronal physiology. The
proposed approach involves a comprehensive, multidisciplinary analysis of neuronal function at the genomic,
epigenomic, organismal, and neural circuit level. The proposed project is significant because it uses innovative
approaches to investigate emerging concepts with major implications for human brain health, age-related
cognitive decline, and neurodegenerative diseases. Further, the project will lead to the development of new
research tools and models. Insights gained from the proposed studies are also expected to inform research and
knowledge in other fields related to genomic stability and aging.

## Key facts

- **NIH application ID:** 10241955
- **Project number:** 5R01AG064363-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Kira Poskanzer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $331,075
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10241955

## Citation

> US National Institutes of Health, RePORTER application 10241955, Role of DNA double-strand breaks in neural function and homeostasis (5R01AG064363-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10241955. Licensed CC0.

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