Longitudinal stability of disease signatures under Therapy: validation of markers and prediction of targets

Principal Investigator

Associated Doctoral Researcher

Associated Principal Investigator

Background and current state of research

In the western world the prevalence of chronic inflammatory disease (CID) is over 10% with an increasing tendency. CIDs are complex, often life-long lasting diseases caused by different factors, such as genetics, environment, microbiota and the immune response. The interaction of those factors plays an important role in the pathogenesis and is not understood so far, thus CIDs can be treated but not cured.

15 scientific collaborators from 9 different countries build the SYSCID consortium, which is funded by the EU for 5 years (started 2017). SYSCID focuses on the development of a systems medicine approach for the prediction of CID. This consortium concentrates on 3 major CID’s: inflammatory bowel disease (IBD), rheumatoid arthritis (RA) and systemic lupus erythrematosus (SLE) in order to identify a common mechanisms contributing their pathogenesis. At Kiel University (CAU) we analyze multiple sample cohorts, including a cross-sectional and a longitudinal study, to describe the shared and unique “core signatures” of the diseases and the therapeutic responses across CID to define molecular biomarkers predicting the response to different therapies. The use of multidimensional, dynamic molecular data approaches could provide more knowledge about CID and create a framework for disease outcome to guide therapeutic decision in the clinic.

Our goals

(1) Identification of “core signatures of disease”

Chronic inflammatory diseases are hypothesized to share molecular mechanisms, based on the use of common therapeutics. The shared core signatures are assumed to be stable under different conditions, such as therapy. In addition to the cross-sectional study, the longitudinal study of CID patient under biologic therapy will provide multi-omics datasets, including RNA and DNA biomaterial, at different time-points. The transcriptome and methylome analysis, in combination with clinical data, will provide information of unique and shared disease activity.

(2) Identification of “dynamic signatures of disease activity” that define therapeutic response and non-response patterns across CID.

The identification of dynamic signatures of the disease will not only help in deciphering the core mechanism, but also the changes under therapy over time. We will test cellular stability of dynamic signatures in the peripheral blood of CID patients, which represent the disease activity. Using the dataset of the longitudinal study, we will distinguish between the patients, who respond to the therapy and the ones who do not to define molecular biomarkers for the response to different therapies. This will enable the clinicans to adapt the therapy on an individual patient level at a very early stage.

(3) Longitudinal single cell signatures as a diagnostic tool to design tailored biological therapy.

The classification of different immune cells, based on the results of (2), will provide detailed information of the molecular signature during inflammation. For this task, mononuclear blood cells from peripheral blood within a prospective cohort of CID patients before and 6 weeks after therapy will be investigated with the help of the SeqWell single cell sequencing protocol.

How to get there

Together with 15 cooperation partners from 9 European countries, the SYSCID consortium provides experienced researchers specialized in different fields. Investigations at various levels provide information of the transcriptome, the methylome, the glycome and the microbiome. The combination of the analyses and the interdisciplinary work between the different members of the consortium offers many possibilities.

Particularly, in Kiel we focus on transcriptome sequencing and methylome analysis of two different cohorts: a cross-sectional and a longitudinal study. With over 1500 samples in total, we want to investigate markers for the core signature and the outcome of therapy.

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