# Functional Analysis of MicroRNAs and Target Genes in Immune Tolerance

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $518,979

## Abstract

Project Summary
Autoreactive B cells play critical roles in many autoimmune diseases. Multiple immune tolerance
checkpoints exist to remove autoreactive B cells or keep them under control. Defects in these checkpoints
constitute the basis for the development of autoimmune diseases. Despite intensive study, our
understanding of these checkpoints remains incomplete and fragmentary. MicroRNAs (miRNAs) are a new
class of small non-coding RNAs that regulate a large diversity of biological processes. Hundreds of miRNAs
are expressed in the immune system. While some miRNAs have been shown to play important roles in
lymphocyte development and function, the roles of miRNAs in controlling immune tolerance remain poorly
understood. We performed in vivo functional analysis of hundreds of miRNAs in the recently established
IgMb-macroself mouse model and identified miR-148a as an important regulator of B cell central tolerance
and autoimmunity (Nature Immunology 17:433-40, 2016). Further molecular analysis identified 119 target
genes regulated by miR-148a in immature B cells. We examined 4 of these target genes and demonstrated
that 3 of them, Gadd45a, Bim and Pten, regulate B cell central tolerance. In this proposal, we will 1) further
investigate the cellular and molecular mechanisms underlying miR-148a regulation of immune tolerance
and autoimmunity, focusing on its role in controlling various B cell tolerance checkpoints and plasma cell
differentiation; 2) evaluate the possibility of treating systemic autoimmunity through miR-148a ablation and
inhibition by genetic and chemical approaches, respectively, and 3) perform an in vitro functional screen of
the other 115 miR-148a target genes to identify novel regulators of B cell tolerance. Our pilot screen has
identified B4galt5 as a positive hit. As B4galt5 is a major enzyme in the glycolipid biosynthesis pathway, we
speculate that this pathway plays important roles in immune tolerance. Therefore, we will elucidate the
function and mechanism of B4galt5 and the glycolipid biosynthesis pathway in controlling B cell tolerance
and autoimmunity.

## Key facts

- **NIH application ID:** 9944441
- **Project number:** 5R01AI137252-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** DAVID NEMAZEE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $518,979
- **Award type:** 5
- **Project period:** 2019-06-05 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944441

## Citation

> US National Institutes of Health, RePORTER application 9944441, Functional Analysis of MicroRNAs and Target Genes in Immune Tolerance (5R01AI137252-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9944441. Licensed CC0.

---

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