Overview of research projects

Funding: Deutsche Bundesstiftung Umwelt (DBU), 289.350 EUR

Project Details:
Artenreiche Grünlandflächen enthalten auch toxische Pflanzenarten wie Jakobs-Greiskraut (Senecio jacobaea) und Herbst-Zeitlose (Colchicum autumnale), wodurch solche Standorte als Mähwiese zur Futterproduktion auf Grund des Tiergesundheitsrisikos unbrauchbar werden.
Daher wird im ersten Teil des Projekts die Ursache für das Aufkommen dieser Giftpflanzen untersucht. Welche Rolle spielen Bodenparameter und Vegetation bei der heterogenen Verteilung der Pflanzenarten auf einer Wiese und gibt es Unterschiede im Toxingehalt innerhalb der Greiskraut- und Zeitlosen-Population?
Der zweite Teil des Projekts umfasst einen Tierversuch, bei dem die Aufnahme oder Selektion von Greiskraut und Zeitlose und zusätzlich Johanniskraut; Hypericum perforatum) im Heu bei einer ad libitum Fütterung von Pferden untersucht wird. Um gesundheitliche Risiken auszuschließen, führt eine mögliche Aufnahme zum Ausschluss des Tieres aus dem Versuch, weshalb das Fressverhalten genau beobachtet und zusätzlich mit Kameraaufnahmen überwacht wird.

Cooperation Partners:

Gesellschaft für Naturschutz und Auenentwicklung e.V. (GNA),

Veterinärmedizinische Fakultät Universität Leipzig

Funding: DFG Sonderforschungsbereich 900 "Mirkobielle Persistenz und seine Kontrolle""", 215.000 EUR

Project Details:
The early steps of hepatitis C virus (HCV) cell entry involve a complex interplay between the incoming virion and host cell expressed factors. Key host factors in the early phase of HCV cell entry include scavenger receptor class B member 1 (SR-BI), low-density lipoprotein receptor (LDLR) and CD81. Work from the previous funding period has revealed how genetic variation in one host factor, the high-density lipoprotein (HDL) receptor SR-BI, can modulate HCV infection, while highlighting at the same time that to fully understand the mechanisms of early HCV-cell interactions a broader view of the host cell molecules involved is required. In particular, others and we demonstrated that HCV host factors interact with each other and with cholesterol and this critically determines susceptibility. Moreover, we have identified CD81-binding partners calpain-5 (CAPN5) and casitas B-lineage lymphoma proto-oncogene b (CBLB) as novel modulators of HCV entry.
The proposed project for the next funding period has the overarching goal to better characterize how the host factors involved in the early phase of HCV entry interact with the virus and each other, and how these interactions are modulated by genetic and pharmacological factors. The project has four parts: (1) We will evaluate coding SR-BI and CD81 variants in a LDLR/SR-BI negative or - respectively - CD81 negative context for their effect on the HCV replication cycle and especially the early phase of cell entry in vitro. (2) We will determine how selected CD81 variants influence the interaction between CD81 and SR-BI and to what extent this mechanistically explains cell entry phenotypes. Here we will cooperate with project A6 (Pietschmann) which focusesl conversely on variation in SR-BI and membrane cholesterol content. (3) We will investigate how statins and other lipid lowering drugs including the new and highly potent monoclonal antibodies directed at proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of LDLR subcellular localization and function, impact HCV infection. Specifically, we will address the impact on the expression level of SR-BI, LDLR and CD81 and on membrane and cellular cholesterol content of hepatocytes as well as the impact of statin therapy on viral load and hepatic inflammation in patients with chronic hepatitis C. (4) Finally, we will extend our analysis to newly identified CD81 interaction partners CAPN5 and CBLB and their role in HCV cell entry and receptor complex regulation beginning with the generation of human variants to probe whether they impact CD81 and SR-BI interactions as well as HCV infection. Taken together, this work holds the promise of a deeper understanding of the mechanistic role of established and newly discovered HCV entry factors during the early phase of HCV cell entry, its modulation by host genetic variants and non-genetic host factors such as exposure to lipid metabolism-modulating drugs and thus of interindividual variability in the course of chronic hepatitis C.

Results:

https://www.sfb900.de/en/

Cooperation Partners:

Prof. Dr. Thomas von Hahn, Klinik für Gastroenterologie, Hepatologie und Endokrinologie und Institut für Molekularbiologie - Medizinische Hochschule Hannover

Funding: DFG, 215.000 EUR

Project Details:
The early steps of hepatitis C virus (HCV) cell entry involve a complex interplay between the incoming virion and host cell expressed factors. Key host factors in the early phase of HCV cell entry include scavenger receptor class B member 1 (SR-BI), low-density lipoprotein receptor (LDLR) and CD81. Work from the previous funding period has revealed how genetic variation in one host factor, the high-density lipoprotein (HDL) receptor SR-BI, can modulate HCV infection, while highlighting at the same time that to fully understand the mechanisms of early HCV-cell interactions a broader view of the host cell molecules involved is required. In particular, others and we demonstrated that HCV host factors interact with each other and with cholesterol and this critically determines susceptibility. Moreover, we have identified CD81-binding partners calpain-5 (CAPN5) and casitas B-lineage lymphoma proto-oncogene b (CBLB) as novel modulators of HCV entry.
The proposed project for the next funding period has the overarching goal to better characterize how the host factors involved in the early phase of HCV entry interact with the virus and each other, and how these interactions are modulated by genetic and pharmacological factors. The project has four parts: (1) We will evaluate coding SR-BI and CD81 variants in a LDLR/SR-BI negative or - respectively - CD81 negative context for their effect on the HCV replication cycle and especially the early phase of cell entry in vitro. (2) We will determine how selected CD81 variants influence the interaction between CD81 and SR-BI and to what extent this mechanistically explains cell entry phenotypes. Here we will cooperate with project A6 (Pietschmann) which focusesl conversely on variation in SR-BI and membrane cholesterol content. (3) We will investigate how statins and other lipid lowering drugs including the new and highly potent monoclonal antibodies directed at proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of LDLR subcellular localization and function, impact HCV infection. Specifically, we will address the impact on the expression level of SR-BI, LDLR and CD81 and on membrane and cellular cholesterol content of hepatocytes as well as the impact of statin therapy on viral load and hepatic inflammation in patients with chronic hepatitis C. (4) Finally, we will extend our analysis to newly identified CD81 interaction partners CAPN5 and CBLB and their role in HCV cell entry and receptor complex regulation beginning with the generation of human variants to probe whether they impact CD81 and SR-BI interactions as well as HCV infection. Taken together, this work holds the promise of a deeper understanding of the mechanistic role of established and newly discovered HCV entry factors during the early phase of HCV cell entry, its modulation by host genetic variants and non-genetic host factors such as exposure to lipid metabolism-modulating drugs and thus of interindividual variability in the course of chronic hepatitis C.

Cooperation Partners:

Prof. Dr. Thomas von Hahn

Klinik für Gastroenterologie, Hepatologie und Endokrinologie und Institut für Molekularbiologie - Medizinische Hochschule Hannover

Project Details:
Respiratory multifactorial diseases cause problems in swine populations worldwide. Pathogens as porcine circovirus type 2 (PCV2) and Mycoplasma hyopneumoniae (M. hyopneumoniae)may be involved in disease development in combination with management, husbandry, and environmental factors. In a conventional farm, where piglets were not vaccinated against PCV2, it will be examined to what extent the introduction of vaccination against PCV2 has an effect on animal health. In addition the effect of the used combinaory vaccine (PCV2+M.hyopneumoniae) will be evaluated in comparison to simultaneously administered mono- vaccines against PCV2 and M. hyopneumoniae.
In a two-phase trial, 524 (phase 1) or 521 (phase 2) clinically healthy piglets are included at the first week of life. In the first phase, performance parameters will be compared in animals vaccinated against M. hyopneumoniae only (group A) or vaccinated against PCV2 and M. hyopneumoniae (group B). In phase 2, vaccinations against PCV2 and M. hyopneumoniae with different vaccines are compared (groups C and D). Performance parameters recorded will include total losses, daily weight gains during suckling, rearing, and fattening, and pathogen loads in serum (PCV2) or tracheobronchial secretions (M. hyopneumoniae). In addition, lungs are assessed at slaughter.

Funding: Ministerium für Energiewende, Landwirtschaft, Umwelt, Natur und Digitalisierung des Landes Schleswig Holstein., 10.000 EUR

Project Details:
Dieses Projekt hat zum Ziel, geeignete Tötungsmethoden für Ferkel unter 30 kg, bei denen aus Tierschutzgründen eine Tötung erforderlich ist, hinsichtlich ihres praktischen Einsatzes im Betrieb zu bewerten.

Funding: DFG, 449.000 EUR

Project Details:
In this research project, the effects of Ascaris suum infections in pigs on the intestinal transport of nutrients will be investigated. This will be achieved by in vitro measurements on intact epithelium via the electrophysiological response after mucosal addition of nutrients, via flux studies using radiolabelled substrates and via uptake studies in membrane vesicles of the luminal and basolateral membrane of enterocytes. These functional studies are complemented by molecular biology studies on the expression of the transport systems (quantitative RT-PCR, Western blot and immunohistochemistry).

Results:

Koehler, S., Springer, A., Issel, N., Klinger, S., Wendt, M., Breves, G., Strube, C. (2023) Effects of adult Ascaris suum and their antigens (total and trans-cuticular excretory-secretory antigen, cuticular somatic antigen) on intestinal nutrient transport in vivo. Parasitology 150, 78-87

 

Koehler, S., Springer, A., Issel, N., Klinger, S., Wendt, M., Breves, G., Strube, C. (2021) Ascaris suum nutrient uptake and metabolic release, and modulation of host intestinal nutrient transport by excretory-secretory and cuticle antigens in vitro. Pathogens 10, 1419

 

Koehler, S., Springer, A., Issel, N., Klinger, S., Strube, C., Breves, G. (2021) Changes in porcine nutrient transport physiology in response to Ascaris suum infection. Parasite & Vectors 14, 533

Funding: QOL Med LLC,Vero Beach, Florida, USA; Unrestricted Research Grant , 230.000 EUR

Project Details:
Current concepts of genetically-determined carbohydrate malabsorption have implicated homozygous and compound heterozygous mutations in the gene encoding SI as the molecular basis for the onset of this intestinal disorder (Naim et al., J Pediatr Gastroenterol Nutr. 2012 Nov;55 Suppl 2:S13-20. review). The major pathogenic variants in CSID are: V577G in the isomaltase subunit and G1073D, F1745C and R1124X in the sucrase subunit, whereby the G1073D is the mutation with the highest prevalence among CSID patients. We have recently suggested that the symptoms and clinical phenotype in CSID follow a gradient of severity that is directly associated with the cellular trafficking patterns of SI mutants between the ER, Golgi and cell surface (Gericke et al., Biochim Biophys Acta. 2017 Mar;1863(3):817-826). Interestingly, some of the mutations analysed occur as heterozygotes in these patients. Along similar lines is the finding that 5 out of 11 patients in our study by Sander et al. (Hum Mutat. 2006 Jan;27(1):119.) occur as heterozygotes towards mutations of the SI gene and harbor mutations such as G1073D, F1745C and T694P.

Funding: Bundesministerium für Ernährung und Landwirtschaft, 682.563 EUR

Project Details:
Unter standardisierten Versuchsbedingungen mit Einzeltierhaltung werden Akzeptanz und Verdaulichkeit sowie Auswirkungen auf die Magen-Darm-Gesundheit junger Mastschweine geprüft, in deren Mischfutter die Komponente Weizen (ca. 70 %) in zunehmenden Anteilen durch Roggen ersetzt wurde. Damit wird eine vergleichende Bewertung der beiden Schwergetreidearten in der Mastschweinefütterung ermöglicht.

Cooperation Partners:

Institut für Tierernährung, Freie Universität Berlin

Institut für Tierernährung, Universität Bonn

KWS LOCHOW GmbH, Bergen/Wohlde

Funding: Europäische Innovationspartnerschaft "Produktivität und Nachhaltigkeit in der Landwirtschaft"" (EIP Agri) über Kompetenzzentrum Ökolandbau Nds. GmbH", 101.364 EUR

Project Details:
Turkey farming plays an essential role in the production of poultry meat in Germany. The animals are mainly kept on very specialised farms, as the animals make high demands on feed and management. The aim of this project is to cross a robust turkey from genetics and old breeds available on the market. The animals should be healthy, hardy and suitable for keeping under extensive conditions, e.g. also on mixed farms. An essential aspect for the development of the animals is the rearing. In the rearing of turkey chicks, it is currently common practice to incubate eggs artificially. After hatching, the chicks are usually kept in larger groups without the presence of an adult animal or a mother hen. In this project, the conventional hand rearing will be compared with a mother-led rearing, in particular the behaviour of the animals will be investigated with regard to stress resistance, activity, foraging behaviour, fearfulness and social behaviour.

Cooperation Partners:

Kompetenzzentrum Ökolandbau Niedersachsen GmbH, Putenzucht Klein Süstedt i. G., Farmpark-Consult, Bauckhof Fleischmanufaktur GmbH, Öko-Beratungsgesellschaft mbH - Naturland Fachberatung, Bäuerliche Gesellschaft - Demeter im Norden e. V., Ulrike Hoffmeister & Dorothee Hoenig GbR, Praxisbetriebe

Funding: NIH, 318.177 EUR

Project Details:
To achieve a comprehensive mapping of the detailed autonomic, sensory and intrinsic innervation of the colon we have brought together a multidisciplinary team of world experts who have developed breakthrough methodological approaches to assess intrinsic and extrinsic innervation as well as functional circuitry. These recent advanced technologies include the use of tissue clearing (CLARITY), optogenetics, viral tracing, and a miniaturized microelectrode array device capable of a wide range of stimulation parameters, high-resolution microscopy and fiber-optic manometry catheter, as well as laser capture microdissection combined with NanoString nCounter techniques to map the molecular profiling of enteric neurons. These approaches will be applied to define molecular identity of ENS neurons, functional connectivity, detailed autonomic and sensory neuroanatomy, identification of ENS neurons projecting to target colonic cells and influence of different type of electrical stimulation on colonic function (secretion, permeability, motility, afferent nerve modulation). This will provide the foundation of the physiological mechanisms regulating the large intestine and the basis for a strategic development of efficacious treatment for the many intractable colonic disorders.

Cooperation Partners:

Flinders University (AU), University of California Los Angeles (USA), University of Nevada School of Medicine (USA) and Technical University of Munich (DE)