The role of the extracellular matrix protein fibronectin in the development of liver fibrosis

• Applicant: Professorin Dr. Inaam Nakchbandi
• Subject Area: Gastroenterology
• Term: from 2012 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 207660558

Liver fibrosis develops when an insult to the liver results in production and accumulation of extracellular matrix proteins that disrupt the microarchitecture of the liver and interfere with its functions. This is mediated among other things by the release of profibrotic substances such as TGF-beta and possibly by the recruitment of immune cells. Despite significant progress in understanding how fibrosis develops, several key questions remain unanswered. The proposed project aims to answer two of these questions. In the first aim we will initially evaluate how matrix composition affects the fibrotic response. This will be accomplished by comparing the characteristics and the extent of fibrosis from our experiments on preventing fibronectin aggregation to those of directly preventing collagen accumulation. We will then evaluate how signaling of beta1 integrin, a major receptor involved in transmitting signals from the matrix into the cell crosstalks with the major profibrotic signaling pathway, namely TGF-beta-mediated signaling. In the second aim we will assess the contribution of myeloid cells to fibrosis. We will expand our knowledge on the role of myeloid-derived cells on fibrosis progression and take advantage of our preliminary findings in fibronectin conditional knockout mice in order to modify their immune signature and hence the degree of fibrosis.

• DFG Programme: Research Grants