# Degradation of Toll-Like Receptor 8 by RNF216 in response to plasma MicroRNA’s – A Novel Mechanism Regulating Inflammation in Acute Lung Injury

> **NIH NIH K08** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $162,230

## Abstract

This application is for a K08 Mentored Clinical Scientist Research Career Development Award entitled
“Degradation of Toll-Like Receptor 8 by RNF216 in response to plasma MicroRNA’s – A Novel Mechanism
Regulating Inflammation in Acute Lung Injury”. I am a physician in pulmonary and critical care medicine at
the University of Pittsburgh. I am applying for this award to acquire advanced training in cell biology, translational
research methods, and bioinformatics to develop my career as a physician scientist focused on the study of
acute respiratory distress syndrome (ARDS). The main objective of my proposal is to determine how a novel
Toll-Like Receptor 8 (TLR8) degradation pathway in monocytes regulates severe lung injury. TLR8 is a pattern
recognition receptor that senses immunogenic RNA, including some host-derived plasma microRNA’s. TLR8
activation initiates signaling leading to the secretion of cytokines, contributing to excessive inflammation that is
characteristic of severe ARDS. My preliminary data indicate that TLR8 is degraded in monocytes in a mechanism
dependent on the post-translational modification of ubiquitination. Further, I have identified a candidate ubiquitin-
transferring E3 ligase termed RNF216 responsible for targeting TLR8 for degradation, and I observe that
RNF216 mRNA expression is decreased in patients with ARDS. Lastly, I have identified a subset of circulating
plasma microRNA’s in ARDS subjects that may function as novel TLR8 ligands. The aims of this study are: i) to
define the mechanism regulating TLR8 protein levels by the ubiquitin/proteasome system in monocytes ii) to
determine if RNF216 modulates inflammatory signaling by directing TLR8 degradation and define RNF216
expression in ARDS, and iii) to examine plasma miRNA’s in ARDS subjects as TLR8 ligands. These studies will
provide insight into a novel pathobiologic model whereby TLR8 degradation, regulated by RNF216 mediated
protein ubiquitination, controls inflammation in response to host-derived plasma microRNA’s in ARDS. Plasma
miRNA-induced TLR8 activation, augmented by reduced RNF216 mediated ubiquitination and degradation of
TLR8, may drive excessive inflammation. Thus, modulating TLR8 degradation may be a novel strategy to reduce
excessive inflammatory responses in ARDS. This project will provide me advanced skills in cell biology and
bioinformatic approaches to analyze molecular datasets. I will be trained in translational research methodologies
to strengthen my development into an independent investigator. I have committed mentoring from our Division
Chief, Dr. Rama Mallampalli and a PhD comentor in Dr. Bill Chen. Additionally, my mentoring committee
includes Dr. Robert Lafyatis – an international expert in innate immunity, Dr. Stephen Chan – an authority in
translational miRNA biology, and Dr. Bryan McVerry – a superb translational scientist and member of the Acute
Lung Injury Center of Excellence overseeing the clinical Acute Lung Injury program. My work ...

## Key facts

- **NIH application ID:** 9846227
- **Project number:** 5K08HL144820-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** John W Evankovich
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $162,230
- **Award type:** 5
- **Project period:** 2019-01-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9846227

## Citation

> US National Institutes of Health, RePORTER application 9846227, Degradation of Toll-Like Receptor 8 by RNF216 in response to plasma MicroRNA’s – A Novel Mechanism Regulating Inflammation in Acute Lung Injury (5K08HL144820-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9846227. Licensed CC0.

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