# Arginase-1 signaling after neonatal stroke

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $197,224

## Abstract

PROJECT SUMMARY
This research plan is based on a strong scientific premise that hypoxic-ischemic (HI) brain injury induces brain
arginase-1 (ARG-1) to exhibit selected neuroprotective functions, such as efferocytosis and regenerative scar
formation. In our preliminary studies, we detected spatiotemporal changes in ARG1 expression and activity as
a result of neonatal HI. We have shown ARG1 localized mostly in microglia at the injury site early after injury
performing efferocytosis and persisted in the injury core at later timepoints in the area of the tissue scar. ARG1
inhibition decreased ARG1 efferocytic function and worsened histological outcomes. While ARG1 involvement
in efferocytosis and scar formation in other organs is well documented, ARG1-dependent mechanisms of
efferocytosis and scar formation in the neonatal brain after HI are unknown. I hypothesize that ARG-1 regulates
efferocytosis by providing polyamines for cytoskeleton assembly, and efficient efferocytosis is a crucial process
for regenerative scar formation where ARG1 provides proline for extracellular matrix formation. Using in vivo the
Vannucci procedure (common carotid artery coagulation followed by exposure to hypoxia in P9 mice) to induce
HI, I will test my hypothesis in the following Specific aims: I will define whether HI induces polyamine pathway in
ARG1 microglia, and whether ARG1 inhibition translates to defects in cytoskeleton assembly and performance
of efferocytosis (Aim 1). I will characterize how ARG1 signaling alters cell composition in the scar and production
of the extracellular matrix (Aim 2). I will determine whether efferocytosis is necessary for scar formation, if
changes in ARG1 signaling alter local immune response in the injury core and whether this impacts migration of
progenitor cells to the scar and tissue remodeling (Aim 3). The aims will be conducted using novel techniques,
such as TRAPseq and spatial seqFISH that will significantly improve our understanding of processes in individual
cells and cellular transcriptome in 3D. The proposed project will significantly improve our understanding of
arginase-1 pathway, efferocytosis and tissue regeneration as a modifier of brain hypoxic-ischemic injury. This
project will also significantly advance my scientific growth through learning besides the basics of
neuroimmunology, the multiomics approaches and advanced data analysis necessary for my independent
research career. Dr. Ferriero and I selected outstanding mentors, that together with coursework and research
plans are aligned to address my specific knowledge gaps to ensure my career development as an independently
funded physician scientist and to apply for an R01 at the end of this proposal. The proposed experiments and
timeline are within my capabilities and the capabilities of the laboratory, animal care, and UCSF facilities.

## Key facts

- **NIH application ID:** 10664501
- **Project number:** 1K08NS125042-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Jana Krystofova Mike
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $197,224
- **Award type:** 1
- **Project period:** 2023-04-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10664501

## Citation

> US National Institutes of Health, RePORTER application 10664501, Arginase-1 signaling after neonatal stroke (1K08NS125042-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10664501. Licensed CC0.

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