Research

Funding: Deutscher Akademischer Austauschdienst (DAAD), 48.000 EUR

Project Details:
Alphaviruses (family Togaviridae) are emerging and re-emerging small enveloped RNA viruses, which are transmitted from animal reservoirs to humans by mosquitoes and can cause debilitating joint pain or encephalitis. Depending on the reservoir species and the transmitting
mosquito vector they are found in different geographic regions. While Chikungunya virus (CHIKV) and O?nyong?nyong virus (ONNV) were historically restricted to tropical and subtropical climates, Sindbis virus (SINV) and Ross River virus (RRV) are primarily found in Scandinavia and Australia, respectively. Adaptation of CHIKV to new mosquito vectors and global warming led to the occurrence of the virus in Europe, making it a potential public health problem in Germany and neighboring countries. An
introduction of Venezuelan equine encephalitis virus (VEEV), which is circulating in the Americas and causing neurological symptoms in equids and humans, may also be possible in the future. No human vaccines or antiviral drugs against arthritogenic and neurotropic alphaviruses are on the market to date. This is reflected by a gap of knowledge of the molecular mechanism of the infection process and critical host factors involved in alphavirus infection and cross-species transmission.
Recently, our team found that the phosphatidylserine receptor T-cell immunoglobulin and mucin domain 1 (TIM-1) is a CHIKV attachment factor. Another prominent group of phosphatidylserine receptors is the Tyro3, AXL, and MerTK (TAM) receptor tyrosine kinase (RTK) family comprising the three proteins Tyro3, AXL and MerTK. The physiological function of TIM and TAM receptors is to bind and internalize apoptotic
bodies, which expose phosphatidylserine on the outer membrane leaflet. We could show that TIM-1 but not AXL serves as host factor for CHIKV. Moreover, the TIM-1 phosphatidylserine binding domain termed metal ion ligand binding site (MILIBS) is critical for the host factor function of TIM-1 in the context of CHIKV infection. TIM-1 affects binding as well as internalization of CHIKV particles to human cells. Finally, TIM-1 also enhances CHIKV infection in keratinocytes, which are among the first target cells of the virus after mosquito bite.
We therefore hypothesize that alphaviruses including CHIKV will use phosphatidylserine receptors for cell attachment and entry in reservoir species such as non-human primates and in transmitting mosquito vectors. Moreover, we here aim to clarify if virus produced in insect cells also exposes phosphatidylserine and this aids in infection of human cells, i.e. in cross-species transmission. Lastly, we will elucidate, how
phosphatidylserine becomes exposed on the viral envelope.
Thereby the work will contribute to the understanding of the molecular composition of alphavirus particles, the function of alphavirus attachment factors and the role of apoptotic mimicry in cross-species transmission and consequently emergence of alphaviruses.

Project Details:
Different types of glial cells are present in the nervous system. These cells perform many different functions. For example, microglial cells are involved in immune-responses and synapse formation, while oligodendrocytes are important for insulating axons supporting rapid, long-distance voltage signalling in neurons. During early and late postnatal development, the nervous system undergoes alterations in neuronal morphologies, connectivities and functions. From the various glial functions, it can be inferred that also their shape and function changes during this life span. The quantification of the developmental alterations in glial cells together with the knowledge about neuronal, developmental changes will therefore shed light on the functional interactions between neurons and glial cells. It is best to quantify the development of glial cells in a well-defined neuronal structure, because glial cell densities and orientation can be matched to a defined area and spatial axis. The superior olivary complex in the auditory system offers such a well-defined neuronal structure. Our project aims to determine the cell number of microglia and oligodendrocytes in distinct auditory nuclei during postnatal development. The microglial shape will be quantified and their spatial orientation determined. The number of oligodendrocyte-neuron connections will be analysed in a developmental manner. We will find out whether glial development is adapted to neuronal maturation in specific nuclei or follows an general time course.

Results:

Zacher AC, Hohaus K, Felmy F, Pätz-Warncke C.: Developmental profile of microglia distribution in nuclei of the superior olivary complex. J Comp Neurol. 2023 Oct 14. doi: 10.1002/cne.25547. Online ahead of print.

Project Details:
The cat belongs to the most popular companion animal in Germany. Although cats have a long domestication history, our knowledge of their social and cognitive skills, their communication system as well as their social attachment to humans is limited. Several decades of research on dogs has shown a strong impact of domestication on their social behavior and cognitive skills, whereas our knowledge on the impact of domestication on cat behavior, especially towards humans, is in its infancy. It is generally believed that cats "domesticated themselves" by following their prey (rodents) into human settlements. It is assumed that especially the more bold cats lived closely together with humans, which benefited from their hunting abilities. This differs from the domestication of the dog, which was actively domesticated by humans. This different domestication history is likely to have an influence on social interactions between cats/dogs and humans. In this project, we aim to investigate human-directed communication in cats as well as social attachment between cats and their owners. We are interested in whether cats show a kind of "jealousy behavior" like dogs or if and how they compete for their owners. Furthermore, we investigate the influence of factors such as housing (indoor cats, outdoor cats), sex and hormonal status (neutered, not neutered) on social interactions between cats and between cats and humans.

Project Details:
Durch die Untersuchung soll die Prävalenz von EOTRH beim Islandpferd in seinem ursprünglichen Lebensraum herausgefunden werden. Nachdem eine belgischen Studie Hinweise auf eine erhöhte Prävalenz von EOTRH beim Islandpferd liefert, soll nun festgestellt werden, ob tatsächlich eine Disposition beim Islandpferd vorliegt. Die Lebensbedingungen des Islandpferdes entsprechen in seinem Heimatland nach jahrhundertelanger geographischer und genetischer nahezu vollständiger Isolation immer noch weitestgehend den natürlichen Gegebenheiten in Haltung und Fütterung, wobei der europäische Einfluss in den letzten Jahren auch hier stetig wächst. Auf Grundlage dessen kann jetzt das Auftreten von EOTRH unter verschiedenen Voraussetzungen herausgearbeitet werden.
Vor Ort finden sowohl klinische als auch röntgenologische Untersuchungen statt. Eine ausführliche Anamnese und die Untersuchung bestimmter Blutparameter sollen zu weiteren generellen Erkenntnissen über die Ätiologie dieser Zahnerkrankung führen.

Project Details:
Equine asthma (EA) is the most important lung disease in adult horses. EA is characterised by airway hyperreactivity and chronic neutrophilic inflammation leading to irreversible lung damage
and breathing distress in disease progression. Research on EA endo- and phenotypes is lacking. The diagnosis of mild/moderate EA (mEA, formerly "inflammatory airway disease") and severe
EA (sEA, formerly "recurrent airway obstruction") is made by clinical history, symptoms and neutrophil granulocyte count in tracheobronchial (TBF) / bronchoalveolar (BALF) fluids. This
disregards disease heterogeneity that is present in EA cases, underlies examiner variances and does not provide determined therapy. The leading role of neutrophils in EA is still uncertain. We will investigate whether neutrophil extracellular traps (NETs) are part of the pathogenesis and whether valuable correlations to clinical symptoms and diagnosis finding can be made. Therefore, 24 horses are thoroughly examined and scored as to disease severity and phenotype. NET-formation from blood derived neutrophils will be investigated via NET-induction assay and quantified using immunofluorescence microscopy in diseased versus healthy horses. In addition,NETs in TBF, BALF and bronchial biopsies are investigated and quantification of NET- and inflammatory-markers will be performed.

Funding: DFG, 310.150 EUR

Project Details:
The intermediate nuclei of the lateral lemniscus (INLL) is one of the three nuclei of the lateral lemniscus that process and relay auditory information between the cochlear nucleus, the superior olivary complex and the auditory midbrain. While the function of the other two lemniscal nuclei is at least partially understood the involvement of the INLL in sound processing is largely unknown. Moreover, the transmitter type of INLL neurons seem species specific, as rodents and bats are labelled for glutamatergic and glycinergic markers respectively. From animal models that hear well below and above 2 kHz, like humans, hardly any functional data from this auditory brainstem structure is available. The present anatomical and functional data of the INLL indicates that it might be involved in the integration of auditory information between different frequencies. Such a cross-frequency integration is key process for generating the neuronal representation of our auditory environment. To elucidate the filter functions and functional role of the INLL we propose to investigate the sound processing features of this auditory structure with in vivo single unit electrophysiology. Initially, we will record acoustically evoked responses elicited by a battery of sound stimulations ranging from pure tones to conspecific calls. This stimulation battery allows us to characterize the basic processing features of INLL neurons. In the next step, we will determine the temporal and frequency dependent integration characteristics of INLL neurons. Our preliminary in vivo single unit recordings highlight the temporal filter functions by analyzing modulation transfer functions of stimulated transposed tones. In agreement with existing data from bat, we find evidence for integration of sounds between different sound frequencies. Obtaining deeper insights into the filter functions and integration characteristics will allow us to postulate functional roles of the INLL in sound processing. Finally, we plan to perform whole-cell in vivo recordings to gain mechanistic insight how INLL neurons achieve their processing tasks. Thus, this application will illuminate the functional role of an auditory brainstem structure that is well connected but hardly understood and therefore the proposal will substantially add to our understanding of sound processing and how we generate our auditory world in our brain.

Funding: DFG, 192.000 EUR

Project Details:
Etwa 3 % der Weltbevölkerung ist chronisch mit dem Hepatitis-C-Virus (HCV) infiziert, welches akute und chronische Lebererkrankungen verursacht. Da ein robustes immunkompetentes Tiermodell zur Entwicklung prophylaktischer oder therapeutischer Impfstoffe noch nicht gefunden werden konnte und der Ursprung des HCV schwer zu fassen ist, rückt das dem HCV am nächsten verwandte Virus, das equine Hepacivirus (EqHV) bei Pferden, mehr in den Fokus. Ein verbessertes Verständnis dieses Viruses ist außerdem für die Pferdemedizin von großer Bedeutung, da gezeigt werden konnte, dass auch EqHV akute und chronische Infektionen verursachen kann.
Grund für diese Ausprägung kann eine fehlende hepatische Toleranz sein, die verhindert, dass dauerhaft infizierte Pferde eine robuste zelluläre Immunität aufbauen können. Daher würde ein erweitertes Wissen über die Mechanismen der hepatischen Toleranz helfen, chronischen Infektionen entgegenzuwirken. Hierauf soll die therapeutische Impfung eine Antwort geben, bei der die MVA basierte Vektor-Impfstoff-Technologie verwendet wird. Dabei exprimiert MVA (modified vaccinia virus Ankara) ausgewählte EqHV-Antigene, welche dann in Impfungen vergleichend analysiert werden, um diejenigen Antigene zu finden, die eine ausgewogene zelluläre und humorale antivirale Immunantwort induzieren.
Ziel ist es hierbei, die Immunantwort gegen EqHV bei chronisch infizierten Pferden und die immunologische Wirkung einer therapeutischen Impfung gegen EqHV bei gesunden Tieren zu untersuchen. Darüber hinaus stellt dieses Projekt auch einen potenziellen Nutzen für die Humanmedizin dar und liefert weitere Hinweise auf den Ursprung von HCV.

Funding: Bundesministerium für Ernährung und Landwirtschaft (BMEL), 622.484 EUR

Project Details:
Ziel des Projektes "Evolection" ist, die Züchtungsarbeit von nach dem Prinzip der Wechselkreuzung arbeitenden, selbstremontierenden Sauenbetrieben zu objektivieren und durch eine verbesserte Selektionsentscheidung aufgrund von im Betrieb automatisch erhobenen Massendaten zu optimieren. Mittels Cloud-basierter Datenanalyse von in Sauenbetrieben erhobener Leistungszahlen und der Massendatenanalyse verschiedenster Sensordaten des Betriebs im Sinne eines KI-Systems wird ein objektiv nachvollziehbarer und für jeden Transparenter "Goldstandard-KI" der Züchtungsselektion bei der Schweinezucht mittels Wechselkreuzung etabliert. Damit wird die "züchterische Nase" erfahrener Züchter softwaretechnisch nachgebildet, objektiviert und über die Cloud jedem praktischen Sauenhalter zugänglich gemacht. Auch wird durch die Etablierung neuer Bewertungsparameter wie "Langlebigkeit" und "Mütterlichkeit" der gesellschaftlichen Forderung nach mehr Tierwohl Rechnung getragen und durch die messtechnische Erfassung und Auswertung der Futterverwertung, die Ressourceneffizienz der Schweinehaltung als Gesamtheit verbessert.

Cooperation Partners:

Hölscher + Leuschner GmbH & Co. KG

Funding: Forschungskreis der Ernährungsindustrie e.V. (FEI), 96.588 EUR

Project Details:
Milk is increasingly criticised by the public for causing various diseases in humans. Beta-casomorphin-7 (BCM-7), which is formed from A1 beta-casein during the digestion of milk, is suggested to be responsible for this. Caseins make up the largest proportion of the protein fraction in milk, accounting for about 80% of the total protein. Four types are distinguished, two different alpha-caseins (αS1 and αS2), as well as kappa- and beta-casein. In domestic cattle, 12 different variants of the beta-casein gene (CSN2) are known so far (A1, A2, A3, B, C, D, E, F, G, H1, H2 and I), of which the A1 and A2 variants are the most significant. At the protein level, the A1 and A2 beta-caseins differ in a single amino acid at position 67 (A1: histidine; A2: proline), which is thought to have a significant influence on the structural and thus also functional properties of the proteins. These can influence both the enteric digestibility of the milk and the technological properties during milk processing. The majority of milk marketed in Germany contains varying amounts of A1 and A2 beta-casein and is referred to as A1 milk. A2 milk, on the other hand, comes from A2/A2 homozygous animals and may not contain A1 beta-casein. The BCM-7 produced from A1 beta-casein may be further degraded to BCM-5, both of which are thought to mediate their effects via - and µ-opioid receptors. In A2 milk, however, the production of these BCM peptides is supposed to be significantly lower, although this assumption is still questionable. In the proposed project, therefore, fundamental questions about the effect of BCM-7 and its occurrence (degradation, formation) in milk and milk products should be answered. Therefore in one part of the project BCM-7 will be added to milk before processing to cheese and yoghurt, in another part milk from A1/A1 and A2/A2 cows will be used for processing. At different steps within the production of the cheese and yoghurt BCM-7 contents will be analysed. In further investigations, physicochemical, sensory and microbiological analyses will be performed to determine the extent to which the different milk genotypes influence the quality of the specific milk products.

Cooperation Partners:

Lehrstuhl für Physiologie (Frau Prof. Cornelia Deeg), Lehrstuhl für Klinische Pharmakologie (Prof. H. Ammer) der Ludwig-Maximilians Universität München

Funding: DFG, 249.200 EUR

Project Details:
Ziel des Projektes ist die weitergehende Entwicklung der Komponenten und der Nachweis der Funktionsweise einer Implantat-dirigierten Anlieferung von Wirkstoffen auf der Basis magnetischer Prinzipien. Auf diesem Wege soll eine neuartige Möglichkeit etabliert werden, spezifische Wirkstoffe mittels magnetischer Nanopartikel bedarfsabhängig zu einem frei wählbaren Zeitpunkt an magnetisierbaren Implantaten zu akkumulieren und somit die Wirksamkeit bei reduzierter Patientenbelastung zu erhöhen. Die Vision des Projektes ist der Einsatz dieser Technik für verschiedene Implantattypen, die gezielt magnetisiert werden, um temporär Wirkstoffe an den Zielort zu verbringen. Damit sollen die Wirksamkeit der Substanzen erhöht, systemische Nebenwirkungen verhindert und die Anzahl von Implantatrevisionen minimiert werden.

Results:

https://pubmed.ncbi.nlm.nih.gov/32861030/

https://pubmed.ncbi.nlm.nih.gov/30482189/

https://pubmed.ncbi.nlm.nih.gov/31941495/

https://pubmed.ncbi.nlm.nih.gov/24112871/

Cooperation Partners:

Prof. P. Behrens (Leibniz-Universität Hannover)

Dr. J. Reifenrath (Medizinische Hochschule Hannover)