# Local Skull Marrow Sensing and Response to CNS Inflammation

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $660,792

## Abstract

Cerebrospinal fluid (CSF) drains into venous blood and into meningeal lymphatic vessels. In this application,
we will test the overarching hypothesis that there exists a third CSF exit route via skull channels into the cranial
bone marrow. Three years ago, we described the existence of sub-millimeter channels connecting skull
marrow cavities with the dural vasculature in mice and humans, and that leukocytes produced in the cranial
bone marrow migrate towards the inflamed central nervous system (CNS) through these channels.
Investigating the skull channels further, we recently made the surprising observation of CNS — skull marrow
crosstalk in the opposite direction: fluorescent CSF tracers injected into the cisterna magna migrate through
skull channels in a perivascular fashion and accumulate in specific skull marrow areas distinct from regions
labeled by intravenous blood pool markers. We here propose to systematically study CSF egress through skull
channels in the steady state and in bacterial meningitis, testing the hypothesis that the skull bone marrow is a
privileged site of hematopoiesis that constantly surveys brain health via sampling the CSF for danger signals.
We will begin with a rigorous assessment of CSF skull channel outflow in healthy mice, establishing its route,
size constraints, and the marrow microenvironment receiving CSF. Motivated by our preliminary data showing
bacterial migration through skull channels into the cranial bone marrow, we will then test the relevance of CSF
skull egress in mice with bacterial meningitis induced by Streptococcus pneumoniae, clinically the most
prevalent strain. The work in mice with meningitis will reveal how skull channel CSF drainage changes in
inflammatory CNS conditions. This Co-PI application unites three different labs, creating a unique set of
complimentary expertise in neuroscience, intravital imaging, immunology and hematology. We propose to
leverage custom-developed tools such as advanced imaging of the hematopoietic niche, image-guided single
cell sequencing, non-invasive imaging for phenotyping of infection and inflammation, in combination with the
fields' gold standard assays. The program is based on bold preliminary data, will clarify the importance of
previously unknown CSF signaling to the skull marrow, and potentially advance knowledge in a setting of clear
clinical need, bacterial meningitis.

## Key facts

- **NIH application ID:** 10821446
- **Project number:** 5R01NS127808-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Charles P. Lin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $660,792
- **Award type:** 5
- **Project period:** 2022-07-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10821446

## Citation

> US National Institutes of Health, RePORTER application 10821446, Local Skull Marrow Sensing and Response to CNS Inflammation (5R01NS127808-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10821446. Licensed CC0.

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