Forschung
Arbeitsgruppe Prof. Bäumer
Our research focus is in the field of immunopharmacology. Currently, three pharmacological targets, JAK-STAT-inhibitors, the histamine H4 receptor and the chemokine thymic stromal lymphopoietin (TSLP) are studied with emphasis on treating allergic skin diseases.
The janus kinase (JAK) signaling pathway is utilized by several cytokines involved in inflammation (e.g. IL-4 and IL-6) and itch (e.g. IL-31, TSLP). A JAK1 inhibitor has been recently licensed for the treatment of atopic dermatitis in dogs. We are interested in possibly different immune modulatory profiles of JAK inhibitors and their effect on inflammation and itch in acute and chronic models of atopic dermatitis as well as on sensory nerves (DRG) in vitro. Recently, we discovered a link between JAK and TRPV1 inhibition. TRPV1 (the receptor activated by the active ingredient of hot chilies (capsaicin)) is an important calcium channel involved in the transmission of itch as well as pain.
Investigation on the role of histamine H4 receptor as compared to other receptors in allergic inflammation of the skin
This project is carried out in collaboration with Prof. Dr. Manfred Kietzmann and Dr. Kristine Roßbach from the University of Veterinary Medicine Hannover and Prof. Dr. Ralf Gutzmer and Prof. Dr. Thomas Werfel from the Department of Dermatology, Medical University of Hannover.
Histamine (2 - (4-imidazolyl) ethylamine) is a biogenic amine that is also called a tissue hormone. After the discovery of the histamine H4 receptor (H4R) in 2000, the role of histamine in the formation of the (allergic) inflammation and itching has to be re-visited. The histamine H4 receptor has been functionally characterized in several immune cells involved in allergic diseases. Another important symptom of atopic dermatitis (in dogs as well as in humans) is itch. Itching is mediated via the H4R in mice. Allergen-induced itch can be blocked in mice by the highly selective H4R antagonists. The first functional description of the H4R in skin innervating neurons was done by our group.
Thymic stromal lymphopoietin (TSLP) is an epithelial derived cytokine that plays a central role in the initiation and maintenance of atopic dermatitis. Importantly, very recent studies revealed, that TSLP is also a direct pruritogen and induces itch in mice after injection into the skin. This discovery sheds a totally new light on TSLP as it might be a bridging molecule between inflammation and pruritus, both the pivotal signs of atopic dermatitis. Very little data about TSLP exist in the dog. Current work focusses on the recombinant expression of canine TSLP and development of specific antibodies against TSLP. The peptide and antibodies will be used to investigate the role of TSLP in skin tissue samples of atopic dogs as well as to stimulate nerve cells. This study is supported by grant from Morris Animal Foundation.
Selected publications
Fukuyama T, Ganchingco JR, Mishra SK, Olivry T, Rzagalinski I, Volmer DA, Bäumer W. (2017) Janus-kinase inhibitors display broad anti-itch properties - a possible link through the TRPV1 receptor. The Journal of allergy and clinical immunology. 2017; PubMed [journal] PMID: 28131799 4.
Fukuyama T, Ganchingco JR, Bäumer W. Demonstration of rebound phenomenon following abrupt withdrawal of the JAK1 inhibitor oclacitinib. European journal of pharmacology. 2017; 794:20-26.
Roßbach, K., Schaper, K. Kloth, C., Gutzmer, R. Werfel, T., Kietzmann, M. Bäumer, W. (2016). Histamine H4 receptor knockout mice display reduced inflammation in a chronic model of atopic dermatitis, Allergy, 71(2):189-97.
Cruse G, Yin Y, Fukuyama T, Desai A, Arthur GK, Bäumer W, Beaven MA, Metcalfe DD. Exon skipping of FcεRIβ eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy. Proceedings of the National Academy of Sciences of the United States of America. 2016; 113(49):14115-14120.
Fukuyama, T., Ehling, S., Cook, E., Bäumer, W. (2015). Topically Administered Janus-Kinase Inhibitors Tofacitinib and Oclacitinib Display Impressive Anti-Pruritic and Anti-Inflammatory Responses in a Model of Allergic Dermatitis. J .Pharmacol. Exp. Ther. 354(3):394-405.
Rossbach, K., Nassenstein,C., Gschwandtner, M., Schnell, D., Sander, K., Seifert, R., Stark, H., Kietzmann, M., Bäumer, W. (2011). Histamine H(1), H(3) and H(4) receptors are involved in pruritus. Neuroscience 190: 89-102
Bäumer, W., Roßbach, K., Mischke, R., Reines, I., Langbein-Detsch, I, Lüth, A., Kleuser, B. (2011). Decreased concentration and enhanced metabolism of sphingosine-1-phosphate in lesional skin of dogs with atopic dermatitis –disturbed sphingosine-1-phosphate homeostasis in atopic dermatitis. J. Invest. Dermatol. 131:266-268.
Alle in PubMed gelisteten Publikationen:
https://www.ncbi.nlm.nih.gov/myncbi/1XOM8Vv2Xy253O/bibliography/public/
Arbeitsgruppe Prof. Dr. Sonja Bröer
I am a veterinarian (graduated in 2010 from TiHo Hannover) as well as an internationally well-connected scientist and enthusiastic teacher. I hope to mentor in programs that help students to succeed in their careers (also outside of academic or industry biomedical sciences). Feel free to setup an appointment and stop by my office!
My research in neurosciences and neuropharmacology is inspired by multidisciplinary approaches evaluating the role of the immune system and de- and regeneration of neurons in diseases of the central nervous system. We focus on epilepsy as one of the most common chronic neurological diseases. Seizures can be triggered by various causes, such as infections and intoxications of the central nervous system, genetic predispositions, stroke, and head trauma. Despite the multifaceted etiology current treatment approaches mainly aim to symptomatically suppress seizures and do not treat the underlying cause of disease development and progression. My work is oriented towards identifying new pharmacological targets that could alter processes that are contributing to seizure generation and brain pathology, such as synaptic reorganization, neurodegeneration, and inflammation.
Especially in an inflammatory state the delicate balance of immune cells that are activated or infiltrate the brain after an infection seems to be key to seizure development and neurological damage. I am particularly interested in the innate immune response. Monocytes adopt different functions depending on their activation cues; they might be helpful in promoting tissue repair, but their ability to fight infected cells can be detrimental to the healing of affected tissue. I am working with a model mimicking the infectious etiology of epilepsy, in which we could show that the death of CA1 neurons in the hippocampus, as well as the activation of microglia and the infiltration of peripheral macrophages are biomarkers of seizure development. Together with my previous team in the group of Prof. Dr. Löscher at the TiHo in Hannover, as well as a very successful cooperation with the Dept. of Pathology and the TwinCore Helmholtz Center for Infection Research, I discovered that as early as two days post viral infection macrophages migrate into the brain and simultaneously resident microglia are activated. Further investigation on macrophage reporter mice allowed a more precise differentiation of the involved immune cells and their surface antigens and showed that a sub-population of microglia was no longer distinguishable from migrating macrophages after activation. By using additional genetically modified mice (Ccr2-/- and Cx3cr1-/-) we were able to further elucidate the significance of the individual cell populations for the onset of seizures: Both microglial activation and macrophage invasion independently lead to acute seizures. However, the associated neurodegeneration in the hippocampus could be significantly reduced by switching off one of the cell populations. The mechanisms of seizure formation and neurodegeneration after viral encephalitis appear to be more complex than initially thought and require further studies to be fully understood.
Apart from disease mechanisms, I have a strong interest in researching new translational therapeutic strategies for neurological diseases. In the past few years, I have worked as a leading scientist in a Silicon Valley based biotechnology start-up, Neurona Therapeutics. The company is developing a stem cell-based therapy for neurodegenerative diseases, including epilepsy. I have gained in-depth knowledge about cell-based therapies, but also about building a preclinical program on its successful route towards clinical approval, which I will both integrate into my research and teaching endeavors at the FU.
Selected publications:
Käufer C*, Chhatbar C*, Bröer S*, Waltl I, Ghitab L, Gerhauser I, Kalinke U, Löscher W (2018).
Chemokine receptors CCR2 and CX3CR1 regulate viral encephalitis-induced hippocampal damage but
not seizures.
Proc Natl Acad Sci U S A 115:E8929–E8938.
*contributed equally
Backofen-Wehrhahn B, Gey L, Bröer S, Petersen B, Schiff M, Handreck A, Stanslowsky N, Scharrenbroich J, Weißing M, Staege S, Wegner F, Niemann H, Löscher W, Gernert M (2018).
Anticonvulsant effects after grafting of rat, porcine, and human mesencephalic neural progenitor cells into the rat subthalamic nucleus.
Exp Neurol 310:70-83.
Bröer S, Hage E, Käufer C, Gerhauser I, Anjum M, Li L, Baumgärtner W, Schulz TF, Löscher W (2017).
Viral mouse models of multiple sclerosis and epilepsy: Marked differences in neuropathogenesis following infection with two naturally occurring variants of Theiler’s virus BeAn strain.
Neurobiol Dis 99:121-132.
Bröer S, Käufer C, Haist V, Li L, Gerhauser I, Anjum M, Bankstahl M, Baumgärtner W, Löscher W (2016).
Exp Neurol 279:57-74.
Bröer S, Backofen-Wehrhahn B, Bankstahl M, Gey L, Gernert M, Löscher W (2012).
Vigabatrin for focal drug delivery in epilepsy: bilateral microinfusion into the subthalamic nucleus is more effective than intranigral or systemic administration in a rat seizure model.
Neurobiol Dis 46:362-76.
All publications:
https://www.ncbi.nlm.nih.gov/sites/myncbi/1h57IXY9uzu5e/collections/59872833/public/