Rainer Pepperkok, Julio Saez-Rodriguez, Mikhail Savitski and Matias Simons

Our research interest

Our research aims to identify and understand the signalling events that lead to uncontrolled growth of myofibroblasts and ultimately the onset of chronic kidney disease.

Background

Chronic kidney disease (CKD) affects around 10% of the population in the Western world, has no specific treatment, and leads to kidney failure. Its pathomechanism is organ destruction through fibrosis, a process mainly driven by uncontrolled growth of myofibroblasts that produce large amounts of extracellular matrix. However, its molecular basis is poorly understood. We want to identify and understand the signalling events that lead to uncontrolled growth of myofibroblasts and ultimately the onset of CKD.

We will develop cutting-edge microscopy and microfluidics technologies to study the response of patient biopsies to large numbers of biological perturbations. We will expand our existing readouts to phenotypes and RNA expression. We will analyse the data computationally and link the results to the patient’s pathological status and clinical outcome. For this, we will adapt our methodology (Eduati et al., Nat Commun 2018) to build mechanistic signalling models. These models will be built from the microfluidics perturbation data and existing signalling pathway knowledge (Türei _et al., Nat Methods_2016).

A powerful tool to understand and treat pathophysiologies is the generation of large-scale datasets that report the responses of cells to biological perturbations. A new technology we have developed (Eduati et al., Nat Commun 2018) allows us to perform such studies ex vivo on small biological samples obtained from patients. We used a caspase-3 reporter to the samples as a proxy for apoptosis. Although limited, the reporter data can be used to build mechanistic and predictive models of these pathways. By also including higher content readouts via microscopy and RNA sequencing, we will drastically increase the number of processes that can be analysed.

Goal

Our goal is to understand the pathophysiology of CKD. The immediate outcome will be an understanding of which factors and signalling pathways drive kidney fibrosis, ultimately leading to CKD.

Furthermore, it will reveal common features and differences between the multiple CKD types, and eventually provide biomarkers and novel drug targets that can be taken further into clinical studies.

More generally, we aim to develop a high-content platform for personalised therapy of kidney (and other) diseases.

Collaborators

Claudia Sommerer, Kidney Center Heidelberg

Martin Zeier, Kidney Center Heidelberg