# Non-canonical cGAS signaling in DNA damage response

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $342,681

## Abstract

DNA damage-induced cGAS signaling in Alzheimer's disease
This application is being submitted in accordance with NOT-AG-20-034. Studies proposed in this administrative
supplement request to our funded NIH grant 1R01AI148741 (Non-canonical cGAS signaling in DNA damage
response) will provide novel functional insights into whether DNA damage-driven cGAS signaling activity
contributes to pathogenesis of AD.
Alzheimer's disease (AD) is the most common form of dementia, accounting for about 60-70% of all the dementia
worldwide. Persistent accumulation of DNA damage, one of the hallmarks of aging, has been linked to AD and
numerous neurodegenerative conditions. Accumulation of elevated DNA double-strand breaks (DSBs) in post-
mortem AD patient brain tissue has been reported by multiple studies. Additionally, multiple pre-clinical mouse
models have revealed that increased DNA damage and associated molecular signatures are observed in the
brain, and that appearance of these evidence precedes the onset of neurological symptoms or
neurodegeneration in these animal model. Interestingly reducing DNA damage in animal models has been
shown to ameliorate pathological features of AD. A better understanding of the mechanisms regulating DNA
damage signaling in brain, in the context of AD holds potential for identifying therapeutic targets for the disease.
The innate DNA sensor, cyclic GMP–AMP synthase (cGAS), has recently emerged as a critical responder to
DNA damage wherein cGAS activation initiated by the damaged DNA triggers inflammation and apoptotic
pathways via DDR induction. In this supplement request, we propose to provide new functional insights into
whether DNA damage-induced cGAS signaling activity contribute to pathogenesis of AD. This objective will be
addressed via following Specific Aims:
1. Determine the abundance, activation status and distribution of constituents of cGAS signaling brain tissue
 from donor AD patients and preclinical mouse models of AD.
2. Determine the involvement of cGAMP-STING signaling in Aβ-exposed in microglia cell cultures.
Overall, these studies will introduce the role of cGAS signaling in AD and provide a molecular rationale for
targeting cGAS-STING-driven interferon and DNA damage response signaling in preclinical mouse models. As
such, this supplement request is within the scope of the active parent NIH award and has the potential to
stimulate new studies for examining novel molecular and biochemical mechanisms of cGAS-STING pathway in
AD. We predict that establishing this new pathway in AD will stimulate additional activity on the part of
neuroscientists, immunologists and cell biologists thereby leading to progress in deciphering and potentially
treating AD and related dementias. This supplement will also enable our laboratory to develop a focus on AD by
generating additional experimental data that can be leveraged to submit new proposals focused directly on AD.

## Key facts

- **NIH application ID:** 10287373
- **Project number:** 3R01AI148741-03S1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Nagaraj Kerur
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $342,681
- **Award type:** 3
- **Project period:** 2019-12-05 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10287373

## Citation

> US National Institutes of Health, RePORTER application 10287373, Non-canonical cGAS signaling in DNA damage response (3R01AI148741-03S1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10287373. Licensed CC0.

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