# Fibrinogen-mediated mechanisms of preterm infant brain injury

> **NIH NIH K02** · J. DAVID GLADSTONE INSTITUTES · 2023 · $146,059

## Abstract

PROJECT SUMMARY/ABSTRACT
Preterm infant brain injury is often associated with blood-brain barrier (BBB) disruption and altered maturation
of the central nervous system (CNS) progenitor cells required for normal brain development and myelination.
The molecular signals in the injured microenvironment that inhibit CNS progenitor maturation are not fully
known. Thus, no therapeutic options are available to prevent the developmental disabilities associated with
preterm birth. BBB disruption alters the CNS progenitor niche by allowing blood proteins into the CNS.
Fibrinogen, a blood coagulation protein, crosses a leaky BBB and is a key contributor to neuroinflammation,
glial scar formation, neurodegeneration, and inhibition of CNS repair. We hypothesize that fibrinogen is a
critical component of the microenvironment in preterm infant brain injury that inhibits CNS progenitor cell
maturation to impair brain growth and myelination. Our preliminary studies show: (1) neonatal mice subjected
to chronic hypoxia display prominent cerebellar pathology that includes fibrinogen deposition, myelination
deficits, and impaired cerebellar growth; (2) Intraventricular injection of fibrinogen in neonatal mice disrupts
cerebellar development in vivo; (3) Fibrinogen activates the bone morphogenetic protein (BMP) receptor activin
A receptor type I (ACVR1) in oligodendrocyte progenitor cells (OPCs) to inhibit OPC maturation and
myelination, (4) Fibrinogen inhibits neurogenesis from neuronal progenitor cells in vitro. Our specific aims will
test our working model, whereby fibrinogen deposition after BBB disruption induces ACVR1-mediated BMP
signaling in CNS progenitor cells to inhibit neurogenesis and myelination leading to abnormal
neurodevelopment. In Aim 1, we will define the contribution of fibrinogen to preterm infant brain injury in vivo
using fibrinogen mutant mice. In Aim 2, we will identify the cellular mechanisms that contribute to preterm
infant brain injury at sites of fibrinogen deposition using in vivo two-photon microscopy (2PM). In Aim 3, we will
determine the molecular mechanism of fibrinogen-induced activation of ACVR1 using in vitro binding and
cellular assays. These studies will reveal the molecular link between BBB disruption and failure of CNS
progenitor cell maturation in preterm infant brain injury. My goal is to become an independent physician-
scientist and leader in the field of newborn brain injury. To continue my progress towards this goal, I will build
upon the expertise of the Gladstone Institutes and UCSF to expand my research skills in the following areas:
(1) in vivo 2PM to study the dynamic cellular responses to BBB disruption and fibrinogen deposition in the
neonatal brain, (2) RNA-sequencing and transcriptome analysis to identify fibrinogen-mediated mechanisms of
extrinsic inhibition, and (3) binding assays and inhibitor studies to discover novel fibrinogen receptors on CNS
progenitor cells. The knowledge and experience gained from this...

## Key facts

- **NIH application ID:** 10450658
- **Project number:** 5K02NS110973-04
- **Recipient organization:** J. DAVID GLADSTONE INSTITUTES
- **Principal Investigator:** MARK A PETERSEN
- **Activity code:** K02 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $146,059
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10450658

## Citation

> US National Institutes of Health, RePORTER application 10450658, Fibrinogen-mediated mechanisms of preterm infant brain injury (5K02NS110973-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10450658. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*