Research AG Erkel

Inflammation is a fundamental protective response of the host to tissue injury, trauma, immune reactions and infection that enables the removal of harmful stimuli as well as the healing of damaged tissue. In acute inflammation, the initial response of the body to a stimulus is achieved by increasing the migration of leukocytes and plasma from the blood to the injured areas. Both the innate as well the adaptive immune response are able to resolve the inflammatory process within several days to restore tissue structure and function. In contrast, prolonged or chronic inflammation characterized by persistently activated immune cells can exacerbate tissue damage and underlies many diseases such as rheumatoid arthritis, asthma; bowel disease as well promotes cancer initiation, progression and angiogenesis. These immune cells together with tissue resident fibroblasts, endothelial cells and stromal cells produce a complex network of cytokines (e.g. TNF-α, IL-1, IL-6, TGF-β, etc), chemokines (e.g. IL-8, CXCL-10, MCP-1), lipids and growth factors, which directly affect infiltrating effector cells, resulting in a continuous stimulation, inappropriate survival and retention of these cell populations. Transcription factors of the NF-κB, FOXP3, IRF, AP-1 and STAT families along with epigenetic mechanisms such as DNA methylation and histone modifications have been shown to be involved in the regulation of inflammatory genes. Inhibitors which specifically interfere with components of different intracellular signaling pathways or inhibit the activation of transcription factors responsible for the expression of disease-related genes may therefore have applications as novel therapeutics in patients with chronic inflammatory diseases.

Despite notable success with biopharmaceuticals such as targeting tumor-necrosis factor-α (TNF-α), interleukin-1β (IL-β) or IL-6, there are still major unmet medical needs in the treatment of inflammatory and fibrotic diseases. The available therapies at present (mainly glucocorticoids, non-steroidal anti-inflammatory drugs, disease modifying antirheumatic drugs such as methotrexate, leflunomide or statins) do not cure for example rheumatoid arthritis or atherosclerosis and do not even sufficiently retard disease progression in a majority of patients. A lack of patient and/or disease responsiveness, resistance to long-term treatment and the fact that biopharmaceuticals have to be injected means that other therapeutic approaches have to be developed, that will limit inflammation without having a deleterious side effects such as immunosuppression.

The main aims of our research are:

(1) The identification and isolation of bioactive compounds from natural sources, which interfere with the inducible transcription of disease-related genes with particular reference to inflammation, allergy and cancer.

(2) The development of test systems.

(3) Mode-of-action studies of new compounds inhibiting signal transduction pathways in mammalian cells.

(4) Microarrays analyses to estimate the side-effects of potential new drugs, the identification of cellular targets and signal transduction pathways involved in the transcriptional regulation of inflammatory and fibrosis relevant genes.

(5) Target identification and quantification by chemoproteomics through the use of liquid chromatography–tandem mass spectrometry (LC-MS/MS). Target validation through genetic and biochemical means.