Resolving the Activin A Receptor complex and its endothelial function in Fibrodysplasia Ossificans Progressiva (FOP)
The TGF-β superfamily member Activin A induces signal transduction via two type I (ALK4/7) and two type II (ACVR2A/B) receptors, which upon ligand binding form heterotetrameric receptor complexes and induce phosphorylation of SMAD2/3. Fibrodysplasia Ossificans Progressiva (FOP) is a rare, severely disabling disease characterized by gain-of-function mutations in the Bone morphogenetic protein (BMP) type I receptor ALK2, the most prominent of which is R206H. This arginine to histidine change turns a normally silent ALK2 signaling complex responsive to Activin A, and finally results in aberrant SMAD1/5 signaling leading to heterotopic ossification (HO). While there is no approved treatment for FOP; several treatment options targeting Activin A or ALK2 are in research and development. Previous studies propose an involvement of the endothelium to the progression of FOP, as the aberrant Activin A signaling is recapitulated in FOP ECs. However, 1) the role of ECs in the formation of HO is not yet fully understood, 2) the composition of the receptor complex is not resolved and 3) the detailed molecular and cellular mechanism of Activin A binding to FOP-ALK2 remains to be explored. Therefor the PhD candidate will perform (a): siRNA based approaches, in combination with co-immunoprecipitation experiments to determine the composition of the receptor complexes. Further the applicant will take advantage of an existing SNAP- and HALO-tagged BMP/TGFβ type I and II receptor library, and perform Stimulated Emission Depletion (STED)-based super resolution imaging. Finally the applicant (c) will set-up a new drug screening plat form for yet unapproached targeting strategies, to functionally interfere with both WT and FOP-ALK2 in ECs treated with Activin A and other ligands of the family. This project is particularly interesting for master students with an interest and/or background in signal transduction, imaging and translational research.
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