# Exploring the role of RNA binding proteins in post-transcriptional regulation of macrophage activation

> **NIH NIH R35** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2024 · $480,631

## Abstract

PROJECT SUMMARY
There is increasing appreciation for the role of RNA binding proteins (RBPs) in shaping the transcriptome of
specialized cell types and in helping cells respond to stress. Macrophages are innate immune cells that mount
rapid and robust gene expression programs following detection of pathogen- and damage-associated
molecular patterns (PAMPs and DAMPs). We know that this response is subject to post-transcriptional
regulation at the levels of alternative splicing, alternative polyadenylation, RNA editing, etc. We also know that
many of the RBPs that control post-transcriptional regulation of gene expression in macrophages are
differentially phosphorylated downstream of PAMP and DAMP sensing. We hypothesize that post-translational
modification of RBPs functionalizes them to coordinate the macrophage innate immune response. Tight
regulation is essential for a functional immune response: a weak response may be insufficient to fight infection
whereas a strong response risks cytokine storms, autoimmunity, and chronic inflammation. The role of RBPs in
post-transcriptional regulation of innate immune gene expression remains an understudied feature of this
important aspect of human health and disease. In the next five years, my lab will work to implicate new RBPs
in the macrophage innate immune response and to define new paradigms through which macrophages
reorganize their nuclei to activate innate gene expression. We have identified a cohort of RBPs in the
SR/hnRNP families of splicing regulatory factors that are differentially phosphorylated in macrophages in
response to PAMP/DAMP sensing. In the next funding period, we will work to uncover the molecular
mechanisms through which each of these factors (hnRNP C, hnRNP F, RALY, and U2SURP) influence
macrophage activation. We will study two complexes with the capacity to regulate many macrophage RBPs at
once: the biomolecular condensate/suborganelle known as the nuclear paraspeckle and the nuclear RNA
exosome. Our preliminary data demonstrate that the paraspeckle is dynamically up- and down-regulated over
the course of early macrophage activation, can sequester specific RBPs in response to PAMP sensing, and is
required for proper amplification of key inflammatory transcripts including Il6, Cxcl1, and Cxcl9. We found that
the RNA exosome can control paraspeckle dynamics and is required to maintain normal homeostatic levels of
antiviral transcripts in macrophages. Pursuing these lines of investigation will provide fundamental insights into
how specific RBPs and ribonucleoprotein complexes control the ability of macrophages to sense and response
to pathogens. By furthering our understanding of cellular stress responses and identifying novel nodes that
control of innate immune gene expression outcomes, our work may contribute to efforts to develop
therapeutics to help patients battling immune disorders and infection.

## Key facts

- **NIH application ID:** 10842551
- **Project number:** 2R35GM133720-06
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Kristin Leigh Patrick
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $480,631
- **Award type:** 2
- **Project period:** 2019-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10842551

## Citation

> US National Institutes of Health, RePORTER application 10842551, Exploring the role of RNA binding proteins in post-transcriptional regulation of macrophage activation (2R35GM133720-06). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10842551. Licensed CC0.

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