# Role of RNA-mediated danger signals in regulating TAAD development

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2021 · $449,530

## Abstract

ABSTRACT
Thoracic aortic aneurysms and dissections (TAAD), particularly type A dissections, are a devastating disease,
with an in-hospital mortality rate up to 25%. Although ascending aortic aneurysms and dissections (AADs) may
result from genetic predispositions, more than 70% of cases are sporadic. Currently, surgical repair is the only
available treatment. Development of pharmacological prevention agents remains a challenging task due to poor
understanding of the cellular and molecular mechanisms responsible for pathogenesis of AADs. We have
reported that postnatal deletion of smooth muscle cell (SMC) transforming growth factor-β type I receptors
(Tgfbr1iko) induces AAD formation in male mice. Recently, we developed a novel X-linked Cre line that drives
Tgfbr1iko and AAD formation in female mice with similar efficiency and severity compared to its parental Y-linked
myh11-CreERTM strain. One of the histological hallmarks of AADs is chronic inflammation, characterized by
progressive SMC depletion, immune cell infiltration, and matrix degradation. These events create a perfect
environment for activation of the innate immunity. Specifically, molecules produced by dying SMCs can function
as damage-associated molecular patterns to activate pathogen recognition receptors (PRRs) via autocrine
and/or paracrine signaling, a scenario currently under rigorous experimental and clinical evaluation for other
chronic conditions. Therefore, we explored activation of the innate immunity in our AAD models and obtained
results as follows. 1) AAD formation was associated with RNA oxidation, upregulation of toll-like receptor (TLR)-
7, and SMC necroptosis. 2) AAD-, but not normal aorta-derived RNAs triggered inflammatory response in
immune cells. 3) More importantly, treatment of mice with reagents inhibiting endosomal TLRs attenuated AAD
formation. These novel findings led to our overall hypothesis that self-RNAs trigger TLR7-mediated danger
signals to promote TAAD development. This hypothesis will be tested through two interrelated Specific Aims.
Specific Aim 1 will determine the contribution of self-RNAs to activation of innate immune injury and AAD
formation. Studies under this Aim will address three key issues. 1) What makes self-RNAs pathogenic? 2) How
self-RNAs regulate the RIPK3/pMLKL pathway to induce necroptosis of SMCs? 3) What is the role of necroptosis
of SMCs in AAD formation? Specific Aim 2 will identify PRR(s) that sense self-RNAs to promote AAD formation.
Experiments proposed under Specific Aim 2 will answer two key questions. 1) Are self-RNAs sensed by the
same endosomal TLR member(s) in different type of cells across species (i.e. mouse vs. human)? 2) Is genetic
or pharmacological inhibition of the responsible RNA-sensing TLR(s) sufficient to alter the course of AAD
formation? Our novel AAD mouse models have placed us in a unique position to address these issues with
mouse AADs of either gender. Completion of this project will provide a better un...

## Key facts

- **NIH application ID:** 10218266
- **Project number:** 5R01HL148019-03
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Zhihua Jiang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $449,530
- **Award type:** 5
- **Project period:** 2019-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10218266

## Citation

> US National Institutes of Health, RePORTER application 10218266, Role of RNA-mediated danger signals in regulating TAAD development (5R01HL148019-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10218266. Licensed CC0.

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