Research projects
The tissue architecture is dynamically linked to cellular function in a reciprocal way to ensure proper tissue homeostasis. The extracellular matrix (ECM) is a crucial component of connective tissues, is at the centre of mechanochemical signalling and needs to be dynamically assembled and remodelled into its cell- and tissue-type-specific configuration. Mutations in ECM proteins or components that regulate ECM secretion are known to be causative for severe musculoskeletal disorders and age- related defects such as loose skin and brittle bones. Strikingly, also the pathological overproduction of ECM, called tissue fibrosis, is often a consequence of age-related diseases and organ failure, highlighting the importance of regulated expression and release of ECM proteins in order to maintain tissue physiology and healthy aging. Importantly, the underlying regulatory mechanisms linking cellular signaling pathways and protein secretion remain largely elusive. Despite decades of research on the (patho)physiology of the extracellular matrix, most studies have previously limited their focus on the extracellular regulation of ECM assembly. The secretion of extracellular matrix proteins is a tightly regulated process that needs to be orchestrated between the different compartments in the secretory pathway. Moreover, protein secretion has to be dynamically adapted to changes in the tissue architecture, changes of environmental conditions and mechanical or cellular stresses to ensure tissue homeostasis. Upon synthesis in the endoplasmic reticulum (ER), secreted bulky cargo proteins such as ECM proteins are recognized by the unique cargo receptor TANGO1 at ER exit sites (ERES), a fundamental process for proper export from the ER. TANGO1 is an ER-membrane-resident protein that binds cargo in the ER lumen and recruits COPII components for cargo export from ERES on its cytosolic side. Importantly, however, the molecular mechanisms that govern cargo selection remain poorly understood.
The overall goal of my research group is to identify how ECM secretion, assembly and homeostasis is regulated in healthy cells, and how the dysregulation of this machinery influences tissue architecture in human development and disease as well as how this machinery is changing during ageing.
