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SFB 877:  Proteolysis as a Regulatory Event in Pathophysiology

Subject Area Biology
Chemistry
Medicine
Term from 2010 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 125440785
 
Final Report Year 2022

Final Report Abstract

The human body consists of many trillion cells with many cells dying and many millions of cells being generated by cell division every day. The properties and activities of all these cells needs to be orchestrated by intercellular signaling molecules such as hormones, mediators, growth factors and cytokines. Once the intercellular signal molecules bind to cellular receptors, intracellular signaling is initiated leading finally to changes in gene expression. The majority of intracellular signaling cascades are mediated by posttranslational protein modifications such as phosphorylation, methylation or lipidation. lnterestingly, some signaling cascades also contain proteolytic steps. While the aforemen­ tioned post-translational protein modifications can be enzymatically reverted within milliseconds, proteolytic steps are completely irreversible. Moreover, it should be noted that not only intracellular but also extracellular signaling proteins such as membrane-bound mediators and receptors are subject to proteolytic cleavage. The general aim of the CRC was to analyze such irreversible signaling cascades, which contained proteolytic steps. We wanted to obtain a profound molecular understanding of proteolytic processes in cellular regulation and signaling and to define the involvement of such processes in human pathophysiology. We reasoned that - at least theoretically - such proteolytic steps containing signaling cascades might represent an entirely different and presumably higher level of regulation than the other mentioned, short-lived, post­translational protein modifications. Our hypothesis was that some proteolytic reactions might represent master switches in the regulation of the immune system, in neural development, in neurodegeneration, in apoptosis and in cancer development. The research projects within the CRC877 analyzed extracellular, intramembrane and intracellular proteolytic reactions. The program for the 12 years of the CRC877 was divided in three portions corresponding to 3 four-year funding periods. In the first period we wanted to obtain a molecular under­ standing of the process of proteolytical regulation. The second funding period asked how these proteolytical processes are coordinated. In the final funding period we addressed the question how these regulatory principles can be translationally exploited. The research performed within the CRC877 not only resulted in some fundamental scientific breakthroughs but also in several early and advanced clinical trials with novel therapeutic strategies for the treatment of patients with C1-esterase inhibitor deficiencies (antibody 3F7) or of patients with autoimmune diseases (sgp130Fc, Olamkicept).

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