# Regulation of short-lived myeloid cells by the novel long non-coding RNA Morrbid

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $420,361

## Abstract

PROJECT SUMMARY
Neutrophils, eosinophils and “inflammatory” monocytes collectively account for ~70% of blood leukocytes and
are among the shortest-lived cells in the body. Precise regulation of the lifespan of these myeloid cells is
critical to maintain effective host responses to pathogens while minimizing the deleterious consequences of
prolonged inflammation. However, how the lifespan of these cells is strictly controlled remains largely
unknown. This proposal is focused on a novel long non-coding RNA (lncRNA) we recently discovered that acts
as a molecular `timer' to control the duration of the lifespan of these inflammatory cells. In my recently established
laboratory, we used high-throughput sequencing and a novel bioinformatic workflow to identify Morrbid, a
previously uncharacterized lncRNA that is potently and specifically induced by pro-survival cytokines in
neutrophils, eosinophils and “inflammatory” monocytes. Our preliminary data shows that ablation of Morrbid in
mice leads to a dramatic reduction in the frequency of these cells at steady state as a result of significant
defects in their survival capacity. We found that Morrbid controls cell survival by repressing the transcription of
its neighboring pro-apoptotic gene, Bcl2l11 (Bim), in an allelic-specific manner. In addition, we show that
Morrbid is conserved in humans, highly expressed in human short-lived myeloid cells and alterations in its
levels of expression are associated with hypereosinophilic (HE) pathologies. Thus, defining the molecular
mechanisms by which Morrbid controls short-lived myeloid cell lifespan and the role of this novel lncRNA during
inflammatory responses will likely reveal new therapeutic targets. As lncRNAs are known to target chromatin
modifying complexes to neighboring genes to regulate their expression and Morrbid is potently induced by pro-
survival cytokines, our central hypothesis is that Morrbid integrates pro-survival extracellular signals
with chromatin modification pathways to control Bcl2l11 expression and thus short-lived myeloid cell
survival. Aim 1 of this project will define the molecular mechanism by which Morrbid represses Bcl2l11
expression in response to pro-survival cytokines. In aim 2, we will establish the role of Morrbid in controlling the
magnitude of inflammatory responses. For this purpose, we will first use mouse strains with different levels of
Morrbid to determine how this lncRNA controls the onset and resolution of eosinophil-mediated lung allergic
inflammation. We will then translate these studies to humans as our preliminary data shows that patients with
hypereosinophic (HE) pathologies have drastically elevated levels of MORRBID. We will use ex vivo eosinophil
culture systems and a humanized mouse model to establish whether MORRBID controls human eosinophil
survival. Moreover, using eosinophils from HE patients we will define whether increased MORRBID levels
contribute to the development of hypereosinophilia. Collectively,...

## Key facts

- **NIH application ID:** 9921479
- **Project number:** 5R01HL136572-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Jorge Henao-Mejia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $420,361
- **Award type:** 5
- **Project period:** 2017-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9921479

## Citation

> US National Institutes of Health, RePORTER application 9921479, Regulation of short-lived myeloid cells by the novel long non-coding RNA Morrbid (5R01HL136572-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9921479. Licensed CC0.

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