Novel anti-fibrotic macrolactones to treat progressive kidney diseases.

• Applicants: Privatdozent Dr. Gerhard Erkel; Professor Dr. Till Opatz; Professorin Dr. Julia Weinmann-Menke
• Subject Area: Nephrology
• Term: from 2017 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 381998846

Renal fibrosis is the ultimate pathological feature of all forms of chronic kidney diseases (CKD) and strongly correlates with the deterioration of kidney function. Fibrosis is associated with loss of epithelial parenchyma, accumulation of myofibroblasts, fibrillary collagen, and inflammatory cells. This complex multistep process is reflected in modulated intracellular signal transduction, changes in cell cell communication and more drastically in an altered differentiation state of cell types like tubular epithelial cells which undergo a partial TGF-beta dependent epithelial-to-mesenchymal-transition that promotes myofibroblast and inflammatory cell recruitment, leading to fibrosis. The incidence of CKD is still increasing worldwide and there is a critical need for new therapeutics that prevent or slow down the progression to end-stage renal disease. The aim of the project is the pharmacological evaluation of the recently identified class of the fungal oxacyclododecindione type of macrolactones and their synthetic derivatives which efficiently inhibit central signaling pathways (e.g. TGF-beta, IL-6) responsible for the initiation and progression of epithelial to mesenchymal transition leading ultimatively to fibrosis. Our approach comprises gene expression and proteome profile based systemic monitoring of treatment based outcomes for disease progression and toxicology in animal models of Lupus-induced glomerulonephritis and ischemia-reperfusion injury. The aim of this project is to obtain genome and proteome wide quantitative experimental data about the dynamic interactions between disease associated components (e .g. EMT-associated genes, transcription factors) in animal models and the identification of novel drug-target interactions in cell culture models after treatment with selected drugs (chemoproteomics). In order to improve the pharmacological potency and selectivity, derivatives of the natural product oxacyclododecindione will be synthesized and tested including the analysis of pro-inflammatory/pro-fibrotic gene and miRNA-expression profiles in vitro in established cell culture models and in vivo in murine models of Lupus glomerulonephritis and ischemia-reperfusion injury. Furthermore, in a toxicogenomical approach, global gene transcription profiling will predict unwanted side effects and toxic responses. Finally results from animal and cell culture experiments will be translated into human system using patient material. With a combination of SystemBiology with ChemicalBiology and the expertise in the pathology and pathophysiology of CKD, we aim to develop new therapeutic concepts not obvious in classical drug development.

• DFG Programme: Research Grants