# Decoding protein MARylation networks in astrocytes using chemical biology approaches

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2021 · $503,036

## Abstract

Project Summary
Astrocytes are critical regulators of innate immunity in the central nervous system (CNS). Stimulation of CNS
innate immunity by neuroinflammatory activators such as pathogens and brain injury, as well as in response to
neurodegeneration, cause astrocytes to undergo a transition to a reactive phenotype called astrogliosis. While it
is well accepted that astrogliosis can act as a protective mechanism to minimize CNS damage, the mechanisms
that regulate astrogliosis are not well understood. Our preliminary results and data from the literature support
our general hypothesis that PARP7 controlled MARylation critically shapes the innate immune responses in
the CNS. Our long-term goal is to understand the role of PARP7 in astrogliosis and whether PARP7 represents
an actionable target for CNS pathologies that arise as a consequence of activation of CNS innate immunity. The
objective of the proposed work is elucidate the mechanisms by which PARP7 regulates innate immunity in
astrocytes. PARP7 has emerged as a critically important member of a large enzyme family known as PARPs,
especially in the innate immune response. Similar to other PARP family members, PARP7 catalyzes the post-
translational modification known as mono-ADP-ribosylation (MARylation), which involves the transfer of
ADP-ribose from NAD+ to amino acids on target proteins. The MARylation targets of PARP7 in astrocytes are
unknown. To decode the mechanisms by which PARP7 regulates innate immunity in astrocyte, we need to
identify the direct targets of PARP7 in astrocytes. Identifying the direct targets of PARP7 has been challenging,
however, due to the fact that PARPs share the same substrate NAD+. To overcome this limitation, we describe
the development of engineered PARP7—orthogonal NAD+ analogue pairs for identifying the direct targets of
PARP7 in astrocytes lysates (Aim I). We also describe the generation of membrane-permeant variants of our
orthogonal NAD+ analogues, which are critical for identifying PARP7 targets in intact astrocytes using stimuli
that activate the innate immune response in astrocytes (Aim II). Lastly, we describe a strategy for improving
the selectivity of PARP7 inhibitors (Aim III). Selective inhibitors of PARP7 are essential chemical probes for
evaluating the function of PARP7-mediated MARylation in the innate immune response in astrocytes. We
anticipate that these studies will not only clarify our understanding of the function of PARP7-mediated
MARylation in innate immunity in astrocytes, but could also lead to new therapeutic strategies for CNS
pathologies, particularly neuroinflammatory (e.g. multiple sclerosis) and neurodegenerative diseases (e.g.
Alzheimer's disease). More generally, the results obtained from these studies will have far-reaching impact on our
understanding of MARylation in cell signaling.

## Key facts

- **NIH application ID:** 10104543
- **Project number:** 5R01NS088629-07
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Michael S Cohen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $503,036
- **Award type:** 5
- **Project period:** 2014-07-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10104543

## Citation

> US National Institutes of Health, RePORTER application 10104543, Decoding protein MARylation networks in astrocytes using chemical biology approaches (5R01NS088629-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10104543. Licensed CC0.

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