Sengle group  

Our overall goal is to investigate the molecular mechanisms through which fibrillin controls BMP growth factor activity and bioavailability.

Our specific aims are:

1. To exactly define and abolish the universal BMP propeptide targeting site within fibrillin
To fully test the importance of BMP-fibrillin interactions for development and postnatal life, mice need to be generated where the BMP propeptide binding site within fibrillin is abolished. To this end, our biochemical studies are directed towards providing the necessary information for establishing BMP binding-negative fibrillin mutant mouse models.

2. To precisely define the molecular requirements necessary for targeting and sequestration of BMP complexes by fibrillin
A comprehensive in-depth study of how molecular interactions between BMP propeptides and BMP growth factors and simultaneously between BMP propeptides and fibrillin occur will reveal the molecular requirements for silencing BMP activity by fibrillin. Moreover, it will provide a better understanding of how dysregulation of growth factor signaling occurs in disease situations wherein microfibrils become subject to proteolytic degradation.

3. To determine whether dominant negative effects on fibrillin microfibrils in vivo leads to release and activation of growth factor signaling
Our previous work contributed significantly to the emerging concept that growth factors of the TGF-β superfamily are targeted and sequestered by fibrillin microfibrils in the extracellular matrix of connective tissues. A logical consequence of this concept is that disruption of fibrillin microfibrils will perturb growth factor signaling. Understanding how growth factor signaling is perturbed is relevant to the pathogenesis of a variety of connective tissue diseases, including Marfan Syndrome. The recently established GT8 mouse line, which carries a truncation mutation of FBN1 fused with an eGFP tag, provides a great opportunity to study the consequences of fibrillin microfibril impairment on growth factor signaling in vivo.

01 März 2011
Gerhard Sengle
Institute for Biochemistry II, Joseph-Stelzmann-Strasse 52, D50931 Cologne
Suggestions and wishes: Gudrun Konertz