During the past 17 years our research has focused on the CLCA gene family and its relevance in disease in humans and animals. CLCA proteins are thought to mediate calcium-activated chloride currents and are obviously involved in many other cellular functions, including mucus production,andhydration of mucus membranes of thenose, trachea and lungrespiratoryas well as theintestinal tractintestineandmodulation ofinnate immune responses. Our group investigates different CLCA family members in humans, mice, horses and pigs to gain a better understanding of their roles in normal and diseased tissues. We aim to understand their pathophysiological relevance in a variety of tissues and therapeutic potential in differentdiseaseschronic inflammatory diseaseswith secretory dysfunction. These diseases, including cystic fibrosis,chronic obstructive pulmonary disease (COPD),asthma, and recurrent airway obstruction (RAO), are characterized by reduced mucous hydration and clogging of airways or the intestinal tract with highly viscous mucus. We hypothesize that members of the CLCA gene family play critical roles in these maladies and may be of interest for novel strategies for intervention and therapy. Our investigations have been financially supported by the German Mukoviszidose e.V., the German Research Foundation (DFG) and other funding bodies.
Within the frame of the DFG-funded Transregional Collaborative Research Center SFB-TR 84 “Innate Immunity of the Lung: Mechanisms of Pathogen Attack and Host Defence in Pneumonia” we help to elucidate mechanisms of early pathogen attack in lung infection. For further details, see: http://www.sfb-tr84.de/ (project Z1b)
Mueller-Redetzky H.C., Felten M., Hellwig K., Wienhold S.-M., Naujoks J., Opitz B., Kershaw O., Gruber A.D., Suttorp N. and Witzenrath M. (2015). Increasing the inspiratory time and I:E ratio during mechanical ventilation aggravates ventilator-induced lung injury in mice. Critical Care 19
Mueller-Redetzky H.C., Wienhold S.M., Berg J., Hocke A.C., Hippenstiel S., Hellwig K., Gutbier B., Opitz B., Neudecker J., Rueckert J., Gruber A.D., Kershaw O., Mayer K., Suttorp N. and Witzenrath M. (2015). Moxifloxacin is not anti-inflammatory in experimental pneumococcal pneumonia. Journal of Antimicrobial Chemotherapy 70: 830-840.
Mueller-Redetzky H.C., Will D., Hellwig K., Kummer W., Tschernig T., Pfeil U., Paddenberg R., Menger M.D., Kershaw O., Gruber A.D., Weissmann N., Hippenstiel S., Suttorp N. and Witzenrath M. (2014). Mechanical ventilation drives pneumococcal pneumonia into lung injury and sepsis in mice: protection by adrenomedullin. Critical Care 18
Hackstein H., Kranz S., Lippitsch A., Wachtendorf A., Kershaw O., Gruber A.D., Michel G., Lohmeyer J., Bein G., Baal N. and Herold S. (2013). Modulation of respiratory dendritic cells during Klebsiella pneumonia infection. Respiratory Research 14
Hocke A.C., Berg J., Becher A., Knepper J., Klauschen F., Toennies M., Bauer T.T., Schneider P., Neudecker J., Rueckert J.C., Gruber A.D., Suttorp N., Hippenstiel S. and Wolff T. (2013). Increased Severity of 2009 Pandemic Influenza A Virus Subtype H1N1 Infection in Alveolar Type II Cells From Patients With Pulmonary Fibrosis Reply. Journal of Infectious Diseases 207: 693-695.
Hoegner K., Wolff T., Pleschka S., Plog S., Gruber A.D., Kalinke U., Walmrath H.-D., Bodner J., Gattenloehner S., Lewe-Schlosser P., Matrosovich M., Seeger W., Lohmeyer J. and Herold S. (2013). Macrophage-expressed IFN-beta Contributes to Apoptotic Alveolar Epithelial Cell Injury in Severe Influenza Virus Pneumonia. PLOS Pathogens 9
Novel nanoscalic drug carriers hold great potential for improved drug delivery to inflammatory and neoplastic skin diseases in humans and animals. Within the DFG funded Collaborative Research Center 1112 “Nanocarriers: Architecture, Transport, and Topical Application of Drugs for Therapeutic Use”, we investigate several aspects of such novel nanocarriers in inflammatory skin diseases, such as psoriasis and atopic dermatitis. For further details see http://www.sfb1112.de (project C03).
Ostrowski A., Nordmeyer D., Boreham A., Holzhausen C., Mundhenk L., Graf C., Meinke M.C., Vogt A., Hadam S., Lademann J., Ruehl E., Alexiev U. and Gruber A.D. (2015). Overview about the localization of nanoparticles in tissue and cellular context by different imaging techniques. Beilstein Journal of Nanotechnology 6: 263-280.
Holzhausen C., Groeger D., Mundhenk L., Donat C.K., Schnorr J., Haag R. and Gruber A.D. (2015). Biodistribution, cellular localization, and in vivo tolerability of S-35-labeled antiinflammatory dendritic polyglycerol sulfate amine. Journal of Nanoparticle Research 17
Boreham A., Brodwolf R., Pfaff M., Kim T.-Y., Schlieter T., Mundhenk L., Gruber A.D., Groeger D., Kai L., Haag R. and Alexiev U. (2014). Temperature and environment dependent dynamic properties of a dendritic polyglycerol sulfate. Polymers for Advanced Technologies 25: 1329-1336.
Ostrowski A., Nordmeyer D., Boreham A., Brodwolf R., Mundhenk L., Fluhr J.W., Lademann J., Graf C., Ruehl E., Alexiev U. and Gruber A.D. (2014). Skin barrier disruptions in tape stripped and allergic dermatitis models have no effect on dermal penetration and systemic distribution of AHAPS-functionalized silica nanoparticles. Nanomedicine-Nanotechnology Biology and Medicine 10: 1571-1581.
Ostrowski A., Nordmeyer D., Mundhenk L., Fluhr J.W., Lademann J., Graf C., Ruehl E. and Gruber A.D. (2014). AHAPS-functionalized silica nanoparticles do not modulate allergic contact dermatitis in mice. Nanoscale Research Letters 9
Holzhausen C., Mundhenk L., Groeger D., Licha K., Haag R., Abram U., Gemeinhardt I., Schnorr J., Donat C. and Gruber A.D. (2012). Biodistribution of radioactively labeled nanoparticles in the mouse. Journal of Comparative Pathology 146: 52-52.
The foreign body reaction against implanted biomaterials involves the interaction of many contributing factors of the living organism and is also majorly influenced by their physical-chemical features. On the one side, the foreign body reaction is necessary for the integration of the materials into the designated tissue while an overshooting foreign body reaction may lead to failure of implantation, fibrosis, scarring and impaired functionality of the material. The targeted design of biomaterials with the clinically required features thus needs understanding of the molecular mechanisms of the foreign body reaction. It is however still difficult to predict the response against a newly designed biomaterial purely based on the knowledge of its physical-chemical surface features. This insufficient knowledge leads to a high number of factors potentially influencing the foreign body reaction, which have to be analyzed in complex animal experiments. Especially macrophages are seen as the main drivers of the foreign body reaction. One of our major goals is therefore to identify the mechanisms of macrophage-driven degradation, acceptance or rejection of biomaterials in vivo.
R. Klopfleisch, Macrophage reaction against biomaterials in the mouse model – phenotypes, functions and markers, Biomaterials, submitted.
R. Klopfleisch, F. Jung. The pathology of the foreign body reaction against biomaterials, submitted.
Frede A, Neuhaus B, Klopfleisch R, Walker C, Buer J, Müller W, Epple M, Westendorf AM. Colonic gene silencing using siRNA-loaded calcium phosphate/PLGA nanoparticles ameliorates intestinal inflammation in vivo. Journal of Controlled Release, 222:86-96, 2016.
Histopathology is still a major tool to analyze and quantify infectious, degenerative or neoplastic diseases in animal models. It includes qualitative diagnoses as well as semiquantitative and quantitative scoring of a lesion`s magnitude. In addition, the analysis of gene expression by immunohistochemistry and immunofluorescence is a valuable tool to analyze the pathogenesis of disease in situ in the in vivo model.
Klopfleisch R. Multiparametric and semiquantitative scoring systems for the evaluation of mouse model histopathology--a systematic review. BMC Veterinary Research 9:123, 2013.
Weinl C., Vega S.C., Riehle H., Stritt C., Calaminus C., Wolburg H., Mauel S., Breithaupt A., Gruber A.D., Wasylyk B., Olson E.N., Adams R.H., Pichler B.J. and Nordheim A. (2015). Endothelial depletion of murine SRF/MRTF provokes intracerebral hemorrhagic stroke. Proceedings of the National Academy of Sciences of the United States of America 112: 9914-9919.
Gronbach K., Flade I., Holst O., Lindner B., Ruscheweyh H.J., Wittmann A., Menz S., Schwiertz A., Adam P., Stecher B., Josenhans C., Suerbaum S., Gruber A.D., Kulik A., Huson D., Autenrieth I.B. and Frick J.-S. (2014). Endotoxicity of Lipopolysaccharide as a Determinant of T-Cell-Mediated Colitis Induction in Mice. Gastroenterology 146: 765-775.
Klymiuk N., Mundhenk L., Wallner K., Wuensch A., Richter A., Plog S., Stehr M., Holzinger A., Kroener C., Kessler B., Kurome M., Zakhartchenko V., Nagashima H., Gruber A.D. and Wolf E. (2012). A novel pig model of cystic fibrosis generated by sequential targeting of CFTR by bacterial artificial chromosome vectors. Reproduction Fertility and Development 24: 232-232.
Wadwa M, Klopfleisch R, Adamczyk A, Frede A, Pastille E, Mahnke K, Hansen W, Geffers R, Lang KS, Buer J, Büning J, Westendorf AM. IL-10 downregulates CXCR3 expression on Th1 cells and interferes with their migration to intestinal inflammatory sites. Mucosal Immunology, doi: 10.1038/mi.2015.132, 2016.
Seiffart V, Zoeller J, Klopfleisch R, Wadwa M, Hansen W, Buer J, Riedel C, Westendorf AM. IL10-Deficiency in CD4⁺ T Cells Exacerbates the IFNγ and IL17 Response During Bacteria Induced Colitis. Cellular Physiology and Biochemistry, 36:1259-73, 2015.
Nadobny J, Klopfleisch R, Brinker G, Stoltenburg-Didinger G. Experimental investigation and histopathological identification of acute thermal damage in skeletal porcine muscle in relation to whole-body SAR, maximum temperature, and CEM43 °C due to RF irradiation in an MR body coil of birdcage type at 123 MHz. International Journal of Hyperthermia, 31:409-20, 2015.
Noe E, Tabeling C, Doehn JM, Naujoks J, Opitz B, Hippenstiel S, Witzenrath M, Klopfleisch R. Juvenile megaesophagus in PKCα-deficient mice is associated with an increase in the segment of the distal esophagus lined by smooth muscle cells. Annals of Anatomy, 196:365-71, 2014.
Saran S, Tran DD, Klebba-Färber S, Moran-Losada P, Wiehlmann L, Koch A, Chopra H, Pabst O, Hoffmann A, Klopfleisch R, Tamura T. THOC5, a member of the mRNA export complex, contributes to processing of a subset of wingless/integrated (Wnt) target mRNAs and integrity of the gut epithelial barrier. BMC Cell Biology, 14:51, 2013.
Ganesh BP, Klopfleisch R, Loh G, Blaut M. Commensal Akkermansia muciniphila exacerbates gut inflammation in Salmonella Typhimurium-infected gnotobiotic mice. PLoS One, 10;8(9), 2013.
The molecular basis of carcinogenesis of mainly canine and feline tumors are investigated in several projects. A major focus is on the search for genes and their products with relevance for the development, diagnosis, prognosis and therapy of tumors in dogs and cats.
Klopfleisch R (ed.), A Short Textbook of Veterinary Oncology / Kurzlehrbuch der Veterinäronkologie, Springer, available from 08/2016
Klopfleisch R, Kohn B, Gruber AD. Mechanisms of tumour resistance against chemotherapeutic agents in veterinary oncology. Veterinary Journal, 207:63-72, 2016.
Klopfleisch R. Personalized medicine in veterinary oncology: one to cure just one. Veterinary Journal, 205:128-35, 2015.
Klopfleisch R, von Euler H, Sarli G, Pinho SS, Gärtner F, Gruber AD. Molecular carcinogenesis of canine mammary tumors: news from an old disease. Veterinary Pathology,48:98-116, 2011.
Delcour N.M., Klopfleisch R., Gruber A.D. and Weiss A.T.A. (2013). Canine Cutaneous Histiocytomas are Clonal Lesions as Defined by X-linked Clonality Testing. Journal of Comparative Pathology 149: 192-198.
Ageing is not a disease per se, but markedly increases the susceptibility to develop disease, including neoplasia. One important aspect in neoplasia is the impact of the ageing microenvironment on the progression of tumors. The accumulation of senescent cells (cells that are in permanent arrest of cell proliferation) is thought to make an important contribution to tumor development.
We investigate the occurrence and association of senescent cells in age associated disease, including neoplasia.
In addition to our ongoing research support to local veterinary clinics and veterinarians, members of our group concentrate on different highly relevant aspects of animal diseases, including novel and emerging diseases. For example, we have discovered and characterized a novel lethal parasitic disease in pigeons (Sarcocystis calchasi; research leader: Dr. Philipp Olias, Aleksandra Zuraw). This novel and dramatic disease has originally emerged in the Berlin area and has recently been found in the US, possibly implicating a gobal threat to pigeons.
Maier K., Olias P., Enderlein D., Klopfleisch R., Mayr S.L., Gruber A.D. and Lierz M. (2015). Parasite distribution and early-stage encephalitis in Sarcocystis calchasi infections in domestic pigeons (Columba livia f. domestica). Avian Pathology 44: 5-12.
Olias P., Maier K., Wuenschmann A., Reed L., Armien A.G., Shaw D.P., Gruber A.D. and Lierz M. (2014). Sarcocystis calchasi has an expanded host range and induces neurological disease in cockatiels (Nymphicus hollandicus) and North American rock pigeons (Columbia livia f. dom.). Veterinary Parasitology 200: 59-65.
Kershaw O., Heblinski N., Lotz F., Dirsch O. and Gruber A.D. (2012). Diagnostic Value of Morphometry in Feline Hypertrophic Cardiomyopathy. Journal of Comparative Pathology 147: 73-83.
Olias P., Mundhenk L., Bothe M., Ochs A., Gruber A.D. and Klopfleisch R. (2012). Iron Overload Syndrome in the Black Rhinoceros (Diceros bicornis): Microscopical Lesions and Comparison with Other Rhinoceros Species. Journal of Comparative Pathology 147: 542-549.
Peer M., Neuhauser S., Klaus C., Kuiper H., Gruber A.D., Distl O., Lischer C. and Handler J. (2012). Laparoscopic Gonadectomy in Two Intersex Warmblood Horses. Journal of Equine Veterinary Science 32: 117-122.
Furthermore, our team members intensely cooperate with clinics and departments of the Faculty of Veterinary Medicine, the Charité – Universitätsmedizin Berlin, the Federal Institute for Risk Assessment (BfR), the Robert Koch Institute (RKI), the Helmholtz Centre Geesthacht in Teltow (HZG), the Helmholtz Centre for Infection Research (HZI) in Braunschweig, the German Cancer Research Center (DKFU) in Heidelberg as well as numerous veterinary medical clinics and practicing veterinarians in Berlin and throughout Germany and Europe.
The department of veterinary pathology offers diagnostic services to the Departments of the Faculty of Veterinary Medicine at the Freie Universität Berlin, veterinary medical clinics and practicing veterinarians as well as private clients and companies.
The diagnostic services include gross and microscopic examination of all companion and farm animals, zoo- and wildlife animals. Poultry can be examined by the Department of poultry diseases. Fish can be examined by the ILAT (Institut für Lebensmittel, Arzneimittel und Tierseuchen, Invalidenstraße 60 in 10557 Berlin, Telefon 030 / 39784 - 367, E-Mail: firstname.lastname@example.org).
At present, our team of pathologists performs approx. 1,000 necropsies on deceased animals and examines over 7,000 biopsies from patients in therapy each year. Furthermore, we offer several specific immunohistochemical and molecular biological laboratory tests for a variety of animal diseases.
For further information, services and forms see Formulare & Dienstleistungen (only available in german).