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A02

Danger signaling pathways in aortic disease

Both calcified aortic valve stenosis (AS) and aortic aneurysm (AA) formation have traditionally been considered a passive consequence of degenerative processes, caused by decades of mechanical stress. However, more recent experimental evidence has rebutted this outdated notion and our current understanding of aortic disease (AD) holds overactive chronic inflammation responsible for the development and progression of the disease. At the core of this process are cellular and biochemical pathways, which are orchestrated through the activation of innate immune mechanisms. The innate immune system is composed of highly conserved “pattern-recognition receptors” (PRRs) that not only sense microbial molecular patterns, but also detect altered or mislocalized self-molecules, also known as danger signals or danger-associated molecular patterns (DAMPs). This family of germline-encoded receptors consists of soluble, membrane-bound, and cytoplasmic receptors, including Toll-like receptors (TLRs), retinoic acid inducible gene I (RIG-I)-like receptors (RLRs), and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). Stimulation of TLRs and RLRs results in the production of proinflammatory gene expression, whilst NLR stimulation can lead to the induction of proteolytic pathways that activate the highly proinflammatory cytokines of the IL-1 cytokine family. Both TLRs and NLRs have been postulated to be involved in the development of aortic disease, where their upregulation and activation leads to the release of proinflammatory cytokines, promoting the progression of the disease.

We hypothesize that activation of the innate immune system is a prerequisite for the chronic inflammatory state that contributes to the development of aortic disease.

We plan to elucidate if and how specific stimulation of distinct danger-signaling pathways contributes to AD and to test therapeutic interventions targeting PRR activation. We believe that TLR3 and NLRP3 represent important TLR and NLR receptors involved in AD, which therefore should be investigated first. In Aim 1, we will focus on the role of TLR3 in AD. Aim 2 will focus on the contribution of cholesterol crystals as endogenous danger-signals in the development of AD. Aim 3 will analyze cholesterol-crystal-triggered and NLRP3 inflammasome-mediated inflammation in AD. Finally, Aim 4 plans to test if pharmacologically manipulation of cholesterol-crystal solubility can be applied for the treatment of aortic disease.

 

A02


A02 Hypothesis: Activation of Toll-like receptor 3 and NOD-like receptor 3 trigger proinflammatory pathways critical for the development of aortic disease.

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