# Role of miRNA Dysregulation on T Cell Differentiation and Function in MS

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $498,925

## Abstract

Abstract
Multiple sclerosis (MS) is an immune-mediated demyelinating disease of the central nervous system (CNS) which can result
in severe neurological deficits. The cause of the disease is unknown, the immune and neurodegenerative mechanisms
underlying the pathophysiology of the disease are poorly understood, and current therapies are only partially effective at
slowing disease progression. There is a tremendous need to investigate novel mechanisms that may be contributing to
disease susceptibility and the pathophysiology of this disease. To this end, my laboratory has performed a large miRNA
profiling study on naïve and effector/memory CD4 T cell in untreated MS patients to determine if miRNA may contribute
to disease susceptibility or progression. MiRNA negatively regulate gene expression via the RNA interference pathway,
and thus play a key role modulating the level of specific proteins in cells. We have identified at least two pathways that
are altered in MS patients that may contribute to their susceptibility to develop MS. First, miRNAs targeting components
of the Th2 cell differentiation pathway were elevated in MS patients T cells, skewing differentiation into pro-inflammatory
Th1 cells. Second, miRNAs targeting the TGFβ signaling pathway limited the differentiation of regulatory T cells. Thus, the
defects observed in MS patients CD4 T cells may be at least partially mediated by miRNA dysregulation. In this proposal,
we will address the following questions. Aim 1: Are MS patients’ CD4 T cells defective in their ability to differentiate
into Tregs in a miRNA-dependent manner? Preliminary data indicates that naïve CD4 T cells from MS patients fail to
efficiently differentiate into Tregs. Using miRNA inhibitors, we will determine if this failure to differentiate into Tregs is
dependent on specific miRNAs over-expressed in MS patients and whether Treg differentiation can be normalized MS
patients’ naïve CD4 T cells. Aim 2: How does over-expression of MS-associated miRNAs affect the development and
progression of CNS autoimmunity in a mouse model? Using EAE, the role of miRNAs that target CD4 T cell differentiation
into effector and regulatory T cells will be analyzed in vivo to complement the human in vitro experiments. Aim 3: Can
expression level of miR-128, which targets both effector and regulatory CD4+ T cells, modulate the risk of CNS
autoimmunity? We found that miR-128 targets proteins in the Th2 and TGFβ signaling pathways, promoting the
differentiation of Th1 cells and preventing the development of Tregs. Using CD4-specific miR-128-/- mice and mice
overexpressing miR-128 in CD4 T cells, we will determine if loss of miR-128 in CD4 T cells minimizes susceptibility to CNS
autoimmunity, normalizes CD4 T cell differentiation into effector and regulatory cells, and thus, is a potential therapeutic
target to correct both effector and regulatory T cell defects in MS. In contrast, we will use mice overexpressing miR-128
in CD4 T cells to det...

## Key facts

- **NIH application ID:** 10094193
- **Project number:** 5R01AI152435-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Amy E Lovett-Racke
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $498,925
- **Award type:** 5
- **Project period:** 2020-02-03 → 2025-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10094193

## Citation

> US National Institutes of Health, RePORTER application 10094193, Role of miRNA Dysregulation on T Cell Differentiation and Function in MS (5R01AI152435-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10094193. Licensed CC0.

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