# Damage Associated Molecular Patterns and Regenerative Failure in MS

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $369,144

## Abstract

Multiple Sclerosis (MS) is a common disabling disease of young adults. Despite intense immune therapies,
relentless progression continues to occur for reasons that are poorly understood. Our overall hypothesis is
that Danger/Damage Associated Molecular Patterns (DAMPs) within MS lesions function to inhibit
remyelination by preventing the maturation of both oligodendrocyte progenitor cells (OPCs) and premyelinating
oligodendrocytes into myelinating oligodendrocytes through activation of the TLR2/MyD88 pathway. We have
previously shown that in the presence of DAMPs OPC maturation into myelinating oligodendrocytes is blocked
and that in constitutive TLR2 knock-out mice, complete remyelination occurs despite the presence of DAMPs.
Our objectives in this application are to provide convincing mechanistic support that DAMPs function in vivo by
directly targeting the oligodendrocyte lineage and to identify small molecule antagonists to the TLR2/MyD88
pathway that promote remyelination in MS relevant preclinical models. In the first aim we will compare
remyelination in mice harboring cell specific deletions of either TLR2 or MyD88 with strain matched wild-type
controls using the chronic cuprizone model. We will assess the impact of TLR2 or MyD88 deletion on the
histopathology relevant to chronic demyelination: microglial phenotype, astrogliosis and astrocytic scar, and
axonal health. In aim two we will test pharmacologic antagonists to the TLR2/MyD88 pathway for their ability
to promote remyelination in MS relevant preclinical models. Using 34 potential TLR2/MyD88 antagonists that
we identified in a high throughput screen of pharmacologically active compounds, we will first validate these
agents as TLR2/MyD88 antagonists and determine their molecular target in the TLR2/MyD88 pathway.
Validated TLR2/MyD88 antagonists will be tested in cerebellar explant organotypic cultures for effectiveness
on promoting remyelination. Compounds that induce remyelination in cerebellar explants will then move
forward for testing in preclinical animal models. Two models of remyelination will be assessed based on their
inherent lack of remyelination under control conditions. The first model is chronic, 12 week, cuprizone, which
fails to effectively remyelinate in contrast to the traditional 6-week cuprizone model. The second model is
stereotactic focal demyelination with the addition of an MS relevant DAMP, which fails to remyelinate. The
value of these models is that they bear clinical relevance to remyelinative failure in MS. Drugs that promote
remyelination in these MS relevant preclinical models will then be investigated in greater detail for their
pharmacologic targets and their impact on the histopathology of remyelination. We chose to screen a library of
pharmacologically active compounds such that agents active in our preclinical models can move forward
directly to phase II clinical trail. The unique features of this project are: 1) identification of DAMP signaling an...

## Key facts

- **NIH application ID:** 9829120
- **Project number:** 5R01NS104350-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** TIMOTHY VARTANIAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $369,144
- **Award type:** 5
- **Project period:** 2017-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9829120

## Citation

> US National Institutes of Health, RePORTER application 9829120, Damage Associated Molecular Patterns and Regenerative Failure in MS (5R01NS104350-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9829120. Licensed CC0.

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