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Research Group Prof. Gruber

CLCA Molecules in Human and Animal Diseases

Lars Mundhenk and Achim Gruber

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.

Selected literature:

  1. Plog S., Klymiuk N., Binder S., Van Hook M.J., Thoreson W.B., Gruber A.D. and Mundhenk L. (2015). Naturally Occurring Deletion Mutants of the Pig-Specific, Intestinal Crypt Epithelial Cell Protein CLCA4b without Apparent Phenotype. PLOS One 10
  2. Dietert K., Mundhenk L., Erickson N.A., Reppe K., Hocke A.C., Kummer W., Witzenrath M. and Gruber A.D. (2015). Murine CLCA5 is uniquely expressed in distinct niches of airway epithelial cells. Histochemistry and Cell Biology 143: 277-287.
  3. Erickson N.A., Nystrom E.E.L., Mundhenk L., Arike L., Glauben R., Heimesaat M.M., Fischer A., Bereswill S., Birchenough G.M.H., Gruber A.D. and Johansson M.E.V. (2015). The Goblet Cell Protein Clca1 (Alias mClca3 or Gob-5) Is Not Required for Intestinal Mucus Synthesis, Structure and Barrier Function in Naive or DSS-Challenged Mice. PLOS One 10
  4. Dietert K., Reppe K., Mundhenk L., Witzenrath M. and Gruber A.D. (2014). mCLCA3 Modulates IL-17 and CXCL-1 Induction and Leukocyte Recruitment in Murine Staphylococcus aureus Pneumonia. PLOS One 9
  5. Bothe M.K., Mundhenk L., Beck C.L., Kaup M. and Gruber A.D. (2012). Impaired Autoproteolytic Cleavage of mCLCA6, a Murine Integral Membrane Protein Expressed in Enterocytes, Leads to Cleavage at the Plasma Membrane Instead of the Endoplasmic Reticulum. Molecules and Cells 33: 251-257.
  6. Mundhenk L., Johannesson B., Anagnostopoulou P., Braun J., Bothe M.K., Schultz C., Mall M.A. and Gruber A.D. (2012). mCLCA3 Does Not Contribute to Calcium-Activated Chloride Conductance in Murine Airways. American Journal of Respiratory Cell and Molecular Biology 47: 87-93.
  7. Plog S., Groetzsch T., Klymiuk N., Kobalz U., Gruber A.D. and Mundhenk L. (2012). The Porcine Chloride Channel Calcium-Activated Family Member pCLCA4a Mirrors Lung Expression of the Human hCLCA4. Journal of Histochemistry & Cytochemistry 60: 45-56.
  8. Plog S., Mundhenk L., Langbein L. and Gruber A.D. (2012). Synthesis of porcine pCLCA2 protein during late differentiation of keratinocytes of epidermis and hair follicle inner root sheath. Cell and Tissue Research 350: 445-453

 

Research on the Innate Immune System of the Lung

Kristina Dietert and Achim Gruber

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)

 

Selected literature:

  1. 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

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. 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

 

Nanocarriers for Improved Drug Delivery in Skin Diseases

Lars Mundhenk and Achim Gruber

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).

 

Selected literature:

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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

  6. 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.

 

A Novel Parasite that Kills Pigeons in Berlin and Spreads Worldwide

Achim Gruber

Starting in 2006, a previously unknown infectious agent has killed a large number of pigeons and caused much concern, particularly among racing pigeon breeders. Together with colleagues of the Institute of Poultry Science, we have discovered and characterized a novel apicomplexan parasite, Sarcocystis calchasi, which causes this complex and lethal disease in pigeons, termed pigeon protozoal encephalitis, PPE. The parasite is transmitted by the Northern goshawk, seems to have spread throughout entire Germany and has now also been observed in the USA. We, together with the group of Michael Lierz at JLU-Gießen, are currently interested in several unresolved issues of this unusual parasitic infection, such as possible threat to other species, including mammalians and people.

 

Selected literature:

  1. Parasite distribution and early-stage encephalitis in Sarcocystis calchasi infections in domestic pigeons (Columba livia f. domestica). Maier K, Olias P, Enderlein D, Klopfleisch R, Mayr SL, Gruber AD, Lierz M. Avian Pathol. 2015;44(1):5-12.

  2. Sarcocystis calchasi has an expanded host range and induces neurological disease in cockatiels (Nymphicus hollandicus) and North American rock pigeons (Columbia livia f. dom.). Olias P, Maier K, Wuenschmann A, Reed L, Armién AG, Shaw DP, Gruber AD, Lierz M. Vet Parasitol. 2014 Feb 24;200(1-2):59-65.

  3. Modulation of the host Th1 immune response in pigeon protozoal encephalitis caused by Sarcocystis calchasi. Olias P, Meyer A, Klopfleisch R, Lierz M, Kaspers B, Gruber AD. Vet Res. 2013 Feb 11;44:10.

  4. Sarcocystis calchasi-associated neurologic disease in a domestic pigeon in North America. Wünschmann A, Armien AG, Reed L, Gruber AD, Olias P. Transbound Emerg Dis. 2011 Dec;58(6):526-30.

  5. High prevalence of Sarcocystis calchasi sporocysts in European Accipiter hawks. Olias P, Olias L, Krücken J, Lierz M, Gruber AD. Vet Parasitol. 2011 Feb 10;175(3-4):230-6

  6. Unusual biphasic disease in domestic pigeons (Columba livia f. domestica) following experimental infection with Sarcocystis calchasi. Olias P, Gruber AD, Heydorn AO, Kohls A, Hafez HM, Lierz M. Avian Dis. 2010 Sep;54(3):1032-7.

  7. Sarcocystis calchasi is distinct to Sarcocystis columbae sp. nov. from the wood pigeon (Columba palumbus) and Sarcocystis sp. from the sparrowhawk (Accipiter nisus). Olias P, Olias L, Lierz M, Mehlhorn H, Gruber AD. Vet Parasitol. 2010 Jul 15;171(1-2):7-14

  8. Sarcocystis species lethal for domestic pigeons. Olias P, Gruber AD, Kohls A, Hafez HM, Heydorn AO, Mehlhorn H, Lierz M. Emerg Infect Dis. 2010 Mar;16(3):497-9.

  9. A novel Sarcocystis-associated encephalitis and myositis in racing pigeons. Olias P, Gruber AD, Heydorn AO, Kohls A, Mehlhorn H, Hafez HM, Lierz M. Avian Pathol. 2009 Apr;38(2):121-8

 

Morphologic Phenotyping of Mouse and Other Animal Models of Human Disease

Olivia Kershaw, Robert Klopfleisch, Achim Gruber

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.

 

Selected literature:

  1. Klopfleisch R. Multiparametric and semiquantitative scoring systems for the evaluation of mouse model histopathology--a systematic review. BMC Veterinary Research 9:123, 2013.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

 

Research Relevant to Clinical Veterinary Medicine

The entire team

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.

 

Selected literature:

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

 

Regional, National and International Cooperations

The entire team

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.

Keywords

  • FU, Freie Universität Berlin, Fachbereich Veterinärmedizin, Institut für Tierpathologie, Institut für Veterinär-Pathologie, WE12