# Exploration of key proteases and validation of biomarkers in genetically triggered thoracic aortic aneurysms

> **NIH NIH R21** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $116,625

## Abstract

PROJECT SUMMARY: Thoracic aortic aneurysms (TAAs) develop as a consequence to abnormal remodeling
of the aortic extracellular matrix (ECM). This process weakens the aortic wall and leads to gross dilation that
typically progresses to rupture in a generally asymptomatic way. There are several well described etiologies that
contribute to the formation and progression of TAA. These include genetic syndromes, as well as, non-syndromic
inheritable predispositions. Current treatment options are limited and consist of surgical reconstruction or endo-
vascular intervention; neither of which address the underlying mechanisms responsible for disease. It is well
described that TAAs are influenced by both intra- and extra- cellular mechanisms that function to regulate matrix
deposition and degradation, in part, through activation of the matrix metalloproteinases (MMPs) and enhanced
TGF-β signaling. Previously, this laboratory identified the membrane-bound type-1 MMP (MT1-MMP) as a key
mediator of TAA formation through its role in both pericellular proteolysis by activation of MMP-2 and intracellular
TGF-β signaling. Furthermore, we demonstrated that phosphorylation of MT1-MMP regulates enzymatic function
by altering its cellular location, thus mediating access to specific substrates, shifting its role in ECM remodeling
and overall progression of TAA. Despite advancements in our understanding of the pathobiology of TAA, these
innovations have yet to be translated into development of screening, diagnosis, tracking, and treatment of TAA.
Therefore, there is an urgent need to not only identify therapeutic targets, but also develop non-invasive methods
for the early detection of TAA preceding life threatening aortic complications. Work from our laboratory and others
have confirmed that specific MMPs, and their endogenous inhibitors (TIMPs) are implicated in the pathogenesis
of TAA, and similar findings have been demonstrated with microRNAs. Preliminary data from our laboratory has
established that theses MMPs, TIMPs, and microRNAs can be directly quantitated in plasma, and levels can be
potentially utilized in an algorithm for screening patients for both the presence and etiological subtype of TAA.
However, little is known in regards to circulating levels of these analytes in individuals with genetically triggered
TAA. Importantly, the established comprehensive biospecimen repository of Genetically Triggered Aortic Aneu-
rysms and Cardiovascular Conditions (GenTAC) is composed of aortic tissue and plasma specimens collected
from individuals of multiple common predispositions linked to TAA. Therefore, we propose an investigation uti-
lizing this resource to derive novel therapeutic and diagnostic strategies for different subtypes of TAA. Accord-
ingly, the central hypotheses of this proposal are that the function of MT1-MMP is altered in different etiological
subtypes of TAA, and these subtypes are distinguishable by a distinct plasma profile of MMPs, TIMPs, and
m...

## Key facts

- **NIH application ID:** 9986890
- **Project number:** 5R21HL148363-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** John S Ikonomidis
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $116,625
- **Award type:** 5
- **Project period:** 2019-08-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986890

## Citation

> US National Institutes of Health, RePORTER application 9986890, Exploration of key proteases and validation of biomarkers in genetically triggered thoracic aortic aneurysms (5R21HL148363-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9986890. Licensed CC0.

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