# Vascular-Glial Signaling in Neurovascular Injury

> **NIH NIH F99** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $47,036

## Abstract

PROJECT SUMMARY
Stroke and traumatic brain injury (TBI) cause alterations to the vasculature, disrupting the neurovascular unit
(NVU) and causing neuroinflammation and neuronal death. In response to vascular damage, glial cells of the
central nervous system (CNS), astrocytes and microglia, produce pro-inflammatory cytokines that can contribute
to neuronal death. However, the specific signaling that connects the damaged neurovasculature to the glial
response after injury remains to be understood. The eye, as CNS tissue, allow us to study the interactions
between the vasculature and glial cells. Similar to human pathology, Retinal Vein Occlusion (RVO) in mice
causes retinal edema, inflammation, and neuronal death; providing a model to study these interactions. Using
this model, previous studies in our lab identified non-apoptotic activation of the protease caspase-9, that is
usually associated with cell death, in the endothelium. Inhibiting caspase-9 or genetically deleting it from the
endothelium, protects the retina from edema and neuronal death. These results indicated that expression of
endothelial caspase-9 (EC Casp9) leads to neurodegeneration after vascular injury. Furthermore, we discovered
that inhibiting caspase-9 significantly reduces the activity of caspase-6 (executioner caspase that can be
activated by caspase-9) in astrocytes, but not microglia. Activation of caspase-6 in astrocytes is associated with
increased cleavage and hyper-aggregation of GFAP and production of pro-inflammatory cytokines. I hypothesize
that non-apoptotic activation of EC Casp9 increases astroglial caspase-6 which will result in the cleavage of
GFAP, production of inflammatory cytokines, and neurodegeneration P-RVO. The long-term objective of this
proposal is to study the role of caspase-9 signaling in vascular-glial communication and its contribution to
increased pro-inflammatory cytokine and neurodegeneration. Studies in EC Casp9 KO mice revealed that EC
Casp9 activates astroglial caspase-6. To further test the role of caspase-9 signaling on vascular-astroglial
communication, we will determine if astroglial caspase-9 (1) is upstream of astroglial caspase-6 and mediates
GFAP cleavage in RVO, (2) increases the production of pro-inflammatory cytokines, and (3) leads to retinal
neuronal death and visual pathway dysfunction. Understanding vascular-glial signaling in neurovascular injury
can help in the discovery of novel therapeutic targets for neuroprotection. The focus of the postdoctoral phase
will be to study caspase signaling in glial cells and its contribution to retinal ganglion loss in Optic Neuritis
associated with Multiple Sclerosis (MS). The ultimate goal of this F99/K00 proposal is to prepare me to be a
principal investigator and study how neuroinflammation is regulated in neurodegenerative diseases of the brain
that also affect the eye. To accomplish these goals, I developed a plan with mentors and collaborators to guide
my specific research and profes...

## Key facts

- **NIH application ID:** 10393789
- **Project number:** 1F99NS124180-01A1
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Crystal Koralis Hrelic Colon
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $47,036
- **Award type:** 1
- **Project period:** 2021-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10393789

## Citation

> US National Institutes of Health, RePORTER application 10393789, Vascular-Glial Signaling in Neurovascular Injury (1F99NS124180-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10393789. Licensed CC0.

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