# Role of complement in TBI

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2022 · —

## Abstract

After initial mechanical insult, traumatic brain injury (TBI) is characterized by a dynamic process of secondary
injury that involves chronic neuroinflammation and which is implicated in long-term cognitive and motor
impairments. It has long been recognized that neuroinflammation is injurious and represents a therapeutic
target for treating TBI. The complement system is a central component of the inflammatory cascade, and while
there is increasing evidence that complement plays an important role in propagating injury after TBI,
complement can also contribute to homeostatic and reparative mechanisms after brain injury. We have shown
that transient injury site-targeted complement inhibition is protective against both TBI and stroke through the
chronic phase, does not interfere with systemic complement activity, and does not interfere with reparative and
regenerative mechanisms. We have also shown continued and high-level complement activation chronically,
and this represents a therapeutic target to prevent ongoing inflammation and injury. This proposal builds on
these findings.
 There are three pathways of complement activation, and there is strong experimental and clinical
evidence that the lectin pathway plays a key role in activating complement and driving injury after both stroke
and TBI, although the role of the lectin pathway in TBI is less well defined. Our first and second aims are to
investigate the role of the lectin pathway of complement activation in triggering neuroinflammation and
promoting neurodegeneration after TBI. We will accomplish this in a clinically relevant paradigm using a novel
targeted inhibitor specific for the lectin pathway. We will use a murine model of moderate to severe controlled
cortical impact. The therapeutic rationale for investigating an inhibitor that is specific for only the lectin pathway
is that if effective, it will be advantageous to inhibit a single pathway rather than all pathways, since there is
less likelihood of disrupting normal immune homeostatic processes and host defense. In aim 3 we will
undertake a more detailed mechanistic analysis of how complement drives secondary injury after TBI.
Specifically, we will investigate the role of a complement-microglial axis in the neurodegenerative loss of
neurons and synapses. Based on our current data, we will investigate the hypothesis that complement-
dependent microlgial activation and complement opsonin-directed phagocytosis results in loss of synapses and
neurons, which results in impaired cognitive and motor recovery, and that these effects are reversed by
complement inhibition.

## Key facts

- **NIH application ID:** 10436780
- **Project number:** 5I01BX004256-04
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** Stephen Tomlinson
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436780

## Citation

> US National Institutes of Health, RePORTER application 10436780, Role of complement in TBI (5I01BX004256-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10436780. Licensed CC0.

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