Matrix Genotyping

Project introduction

Our main goals are:

     

  • to assess the influence of known and novel IPF risk genotypes on disease outcome including collagen composition and properties
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  • to define fibrosis-specific changes in biosynthesis and molecular properties of collagen
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  • to characterize the functional impact of altered collagen composition and properties on adherent cells
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  • to translate these findings into novel prognostic, diagnostic, and therapeutic strategies to directly target fibrogenesis

Source: Claudia Staab-Weijnitz, Helmholtz Zentrum München

Rationale

Idiopathic pulmonary fibrosis (IPF) is one of the most progressive types of organ fibrosis, with a five-year survival rate of 30-50%, poorly understood etiology, and few treatment options. The ultimate pathological feature of lung fibrosis is scarring of the alveolar gas exchange areas, mostly caused by activated fibroblasts and myofibroblasts which excessively deposit extracellular matrix. Collagen is a major structural component of the extracellular matrix, but its exact composition and molecular properties in normal versus fibrotic matrix have not been well-defined. Importantly, all collagens are subject to various post-translational intra- and extracellular maturation steps and scattered findings from research on osteogenesis imperfecta, diabetes, and cancer argue for an important impact of e.g. collagen post-translational modifications on protein-protein and protein-cell interactions. Collectively, these results indicate that specific molecular properties of collagen affect morphology, function, and behaviour of adherent cells.

Scientific direction and aims

We hypothesize that there is a specific disease-driving collagen code in fibrotic extracellular matrix. Our overall aim is therefore to generate a profound understanding on fibrosis-specific changes of collagen composition and properties and their role in disease etiology and progression. More specifically, we intend to characterize fibrosis-related changes and their effects on a detailed molecular and functional level. To this end, we profile patient samples ( bioArchive ) and perform mechanistic analysis in a combination of in vitro, ex vivo, and in vivo models. Ongoing and future projects include the effects of genetic predisposition on collagen biosynthesis and maturation,the elucidation of function and regulation of enzymes involved in these processes, and finally, the functional consequences of collagen alterations in fibrotic disease.

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