# Investigating the Role of Endosomal Toll-Like Receptors in Remyelination

> **NIH NIH F31** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2024 · $36,369

## Abstract

Project Summary/Abstract
The goal of this proposal is to understand how aberrant activation of endosomal toll-like receptor
(TLR) signaling in microglia contributes to demyelinating disease. Regulation of innate immunological
self-tolerance, or the ability of cells to discern “self” from “non-self” has long been studied in the
periphery in autoimmune disorders, especially in the context of nucleic acids (NA). Understanding of
self-tolerance in the central nervous system (CNS), however, has not been thoroughly investigated
despite expression of these NA-sensing TLRs by microglia, the primary phagocyte of the CNS. Published
data from our lab highlights that microglia retain untranslated RNA transcripts from engulfed myelin for
days after phagocytosis in vitro and in human multiple sclerosis patients. Based on these data, I
hypothesized that these retained transcripts could aberrantly activate endosomal TLRs. I, thus, induced
primary demyelination in UNC93B1 -/- mice, which lack functional NA-sensing TLRs, and observed that
these mice remyelinate more efficiently than wildtype. These data suggest that signaling of NA-sensing
TLRs suppresses remyelination during demyelinating disease. Several exciting questions have now
arisen, which I will tackle in this proposal: 1) Is myelin phagocytosis causing aberrant endosomal TLR
signaling? 2) Are microglia the primary cell type driving this response? 3) Does a specific NA-sensing TLR
hinder remyelination? I hypothesize that TLR7 is aberrantly signaling in response to engulfed myelin
RNAs in microglia and suppressing remyelination. To address these questions, I have acquired powerful
in vivo molecular genetic tools to manipulate UNC93B1 and endosomal TLR function. I will first identify
molecular pathways that are changed in microglia in vitro in response to chronic myelin phagocytosis
and test whether these molecules are UNC93B1-dependent (Aim 1a). I will then determine if the
UNC93B1 dependent effects that I observed on remyelination are microglia-specific (Aim 1b). Lastly, I
will identify the endosomal TLR underlying these UNC93B1 effects (Aim 2). I am now in a strong position
to molecularly dissect the role of NA sensing TLRs in remyelination during demyelinating disease, which
has high long-term therapeutic potential. In the process, I will receive training in a variety of microscopy
and molecular genetic approaches, scientific writing and presentation, and data analyses from
coursework as well as mentorship from Dr. Dorothy Schafer with expertise in microglial biology and my
co-mentor Dr. Ann Marshak-Rothstein with expertise in NA-sensing pathways in autoimmune disease.
Together, this will provide a foundation for my future career as an independent academic scientist
focused on innate immune signaling in the CNS.

## Key facts

- **NIH application ID:** 10998577
- **Project number:** 1F31NS139677-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Jacob Maxwell Stillman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $36,369
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998577

## Citation

> US National Institutes of Health, RePORTER application 10998577, Investigating the Role of Endosomal Toll-Like Receptors in Remyelination (1F31NS139677-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10998577. Licensed CC0.

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