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Dysregulated extracellular signaling pathways in aortic aneurysm formation in Marfan syndrome

Marfan syndrome (MFS) is a multisystem connective tissue disorder, which is characterized by aortic root aneurysm formation with a high risk of aortic dissection and rupture as the most life-threatening condition. However, MFS has a high degree of clinical variability with over 3,000 causative fibrillin-1 (FBN1) mutations distributed over all exons, making clear genotype-phenotype correlations impossible. This is also complicated by the fact that rare mutations in FBN1 may lead to clinical features described as opposite to MFS. For instance, we have found a deletion mutation in the N-terminal region of fibrillin-1 that leads to Weill-Marchesani syndrome (WMS), characterized by short stature and thick skin with no cardiovascular involvement. Fibrillin-1 assembles into fibrillin microfibrils (FMF), the tissue form of fibrillin, which serve as supramolecular scaffolds for the linear deposition of elastic fiber building blocks. Elastic fibers organize into elastic lamellae in the aortic media, which are also decorated on their surface by FMF. Over the last years, we could demonstrate that FMF facilitate targeting and sequestration of growth factors of the TGF-β superfamily. These findings have established the importance of FMF in the regulation of growth factor activity and provided a better understanding for the underlying pathomechanisms of fibrillin-dependent disorders (fibrillinopathies).

The biochemical evidence we have gathered, together with findings from mouse models, led to our current working hypothesis that the structural integrity of fibrillin microfibrils defines the activation state and bioavailability of growth factors.

In this proposal, we aim to investigate how structural changes induced by mutations in fibrillin-1 impact FMF architecture, which then translates into an altered activation state of targeted growth factors. This will allow us to elucidate the genotype-phenotype correlations in MFS and therefore open new therapeutic avenues for patients. Aim 1 will investigate how structural alterations in FMF ultrastructure trigger dysregulated growth factor signaling, which is causative for the initiation and progression of aortic disease. For this purpose, we will utilize four different Fbn1 mouse models with defined structural alterations in FMF either triggering or protecting from severe aneurysm formation (Fbn1-/-: severe aneurysm formation; GT8: C-terminal truncation of fibrillin-1: severe aneurysm formation; H1Δ: deletion of the TGF-β anchoring site: no aneurysm formation; WMΔ: deletion of the ADAMTSL binding site: no aneurysm formation). Aim 2 will evaluate whether interference with bone morphogenetic protein (BMP) signaling represents a new therapeutic strategy in aortic aneurysm formation in MFS. Thereby treating GT8 mice with inhibitors of BMP signaling in combination with genetic approaches (cross-breeding to BMP ligand null or SOST null mice) will let us explore new therapeutic avenues for MFS. Aim 3 will investigate whether genetic ablation of MMPs will delay the onset of aneurysm formation in MFS. Since we found the collagenase MMP-13 to be upregulated in the GT8 aorta, we aim to test whether genetic ablation or pharmacological inhibition of MMP-13 will delay the onset and progression of aortic aneurysm in GT8 mice. Aim 4 will develop new methods to analyze structural alterations of FMF in the aortic wall. Comparison of Raman parameters from skin and aortic samples isolated from fibrillin mutant mouse models with defined structural changes in FMF as well as MFS patients will allow us to explore Raman microspectroscopy as a non-invasive and sensitive diagnostic tool for aneurysm initiation and progression.




B09 Hypothesis: Fibrillin microfibrils (FMF) serve as an extracellular integration platform for TGFβ/BMP and wnt signaling. Failed sequestration of BMP prodomain-growth factor complexes (red cross) due to fibrillin-1 mutation (red dots) leads to aberrantly active BMPs triggering upregulation of MMP expression, which in turn leads to elastic fiber and collagen degradation in the aortic wall. FMF were also found to target inhibitors and modulators of wnt signaling.


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