# Mitochondrial Damage-Induced Necroptotic Cell Death in SporadicAscending Thoracic Aortic Aneurysms and Dissections

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $396,250

## Abstract

Project Summary/Abstract (30 lines)
Ascending thoracic aortic aneurysms and dissections (ATAAD) are extremely lethal surgical diseases. ATAAD
occurs either in association with genetic conditions or spontaneously as sporadic ATAAD, which accounts for
more than 80% of ATAAD. Unfortunately, no clinically proven medication is available to prevent sporadic
ATAAD progression. There is a critical need to develop effective pharmacological strategies to treat these diseases. This project focuses on sporadic ATAAD. One of the significant features of sporadic ATAAD is progressive smooth muscle cell (SMC) depletion, for which the underlying mechanisms are poorly understood. Necrotic cell death, a type of cell death characterized by cell swelling and membrane rupture, causes the release of “toxic” molecules from dying cells, leading to further damage of surrounding cells and extracellular matrix and a profound pro-inflammatory reaction. Necrotic cell death is regulated by a programmed process called
necroptosis. Mitochondrial damage, often observed in aged or stressed cells, is a potent trigger for necrotic
cell death. The overall objective of this application is to determine the role of mitochondrial damage and SMC
necroptosis in the development of TAAD; and the extent to which this mechanism represents a therapeutic target against ATAAD. Our central hypotheses are: (1) mitochondrial damage and subsequent release of mtDNA
trigger the cytosolic DNA sensor cGAS-STING-TBK1 signaling pathway, which activates the RIP3-MLKL pathway and induces SMC necroptosis, contributing to aortic damage and ATAAD formation; and (2) reducing mitochondrial damage or inhibiting SMC necroptosis will prevent aortic destruction and ATAAD progression. We
will test these hypotheses via 3 aims. Aim 1. We will test the hypothesis that mitochondrial damage and subsequent release of mtDNA activates the cytosolic DNA sensor cGAS-STING-TBK1 signaling pathway, which in
turn activates the RIP3-MLKL necroptosis pathway, leading to SMC necrotic death. We will perform serial experiments in cultured SMCs to dissect the signaling leading to necrotic cell death (Aim 1B); and evaluate SMC
mitochondrial damage and necrotic cell death in patient tissues by electron microscopy analysis (Aim 1B). Aim
2. We will test the hypothesis that cGAS and RIP3-mediated SMC necroptosis are critically involved in aortic
SMC injury, aortic destruction, inflammation, biomechanical failure, and ATAAD development by comparing
these aspects in WT mice, cGas-/- mice, Rip3-/- mice, and SMC specific Rip3 knockout mice in a sporadic
ATAAD model induced by HFD/Ang II challenge. Aim 3. We will test the hypothesis that pharmacologically reducing mitochondrial damage or necroptosis will prevent aortic destruction and disease progression in our sporadic ATAAD mouse model. The proposed research is significant because it will not only provide novel insight
of the molecular mechanisms of sporadic ATAAD development, but also test new ...

## Key facts

- **NIH application ID:** 9980977
- **Project number:** 5R01HL143359-03
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Scott A LeMaire
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,250
- **Award type:** 5
- **Project period:** 2018-08-15 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9980977

## Citation

> US National Institutes of Health, RePORTER application 9980977, Mitochondrial Damage-Induced Necroptotic Cell Death in SporadicAscending Thoracic Aortic Aneurysms and Dissections (5R01HL143359-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9980977. Licensed CC0.

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