Research Involving Animals – Division of Biomedical Services

2022 news

July 2022

Refining Rabbit Handling

An animal technician from Leicester has been working to refine the handling of rabbits, and was featured in issue 15 of NC3R’s Newsletter Tech3Rs. In this article Alicia speaks about how she developed the idea, and the positive effects it is having on our rabbits.

The Voltage-Gated K+ Channel Kv1.3 Modulates Platelet Motility and α2β1 Integrin-Dependant Adhesion to Collagen

Joy R. Wright, Sarah Jones, Sasikumar Parvathy, Leonard K. Kaczmarek, Ian Forsythe, Richard W. Farndale, Jonathan M. Gibbons and Martyn P. Mahaut-Smith

Kv1.3 is a voltage-gated K+-selective channel with roles in immunity, insulin-sensitivity, neuronal excitability and olfaction. Despite being one of the largest ionic conductances of the platelet surface membrane, its contribution to platelet function is poorly understood. Here we show that Kv1.3-deficient platelets display enhanced ADP-evoked platelet aggregation and secretion, and an increased surface expression of platelet integrin αIIb. In contrast, platelet adhesion and thrombus formation in vitro under arterial shear conditions on surfaces coated with collagen were reduced for samples from Kv1.3−/- compared to wild type mice. Use of collagen-mimetic peptides revealed a specific defect in the engagement with α2β1. Kv1.3−/- platelets developed significantly fewer, and shorter, filopodia than wild type platelets during adhesion to collagen fibrils. Kv1.3−/- mice displayed no significant difference in thrombus formation within cremaster muscle arterioles using a laser-induced injury model, thus other pro-thrombotic pathways compensate in vivo for the adhesion defect observed in vitro. This may include the increased platelet counts of Kv1.3−/- mice, due in part to a prolonged lifespan. The ability of Kv1.3 to modulate integrin-dependent platelet adhesion has important implications for understanding its contribution to normal physiological platelet function in addition to its reported roles in auto-immune diseases and thromboinflammatory models of stroke.

Increased Mitochondrial Proline Metabolism Sustains Proliferation and Survival of Colorectal Cancer

Saif Sattar Alaqbi, Lynsey Burke, Inna Guterman, Caleb Green, Kevin West, Raquel Palacios-Gallego, Hong Cai, Constantinos Alexandrou, Ni Ni Moe Myint, Emma Parrot, Lynne M. Howells, Jennifer A. Higgins, Donald J. L. Jones, Rajinder Singh, Robert G. Britton, Cristine Tufarelli, Anne Thomas and Alessandro Rufini

Research into the metabolism of the non-essential amino acid (NEAA) proline in cancer has gained traction in recent years. The last step in the proline biosynthesis pathway is catalyzed by pyrroline-5-carboxylate reductase (PYCR) enzymes. There are three PYCR enzymes: mitochondrial PYCR1 and 2 and cytosolic PYCR3 encoded by separate genes. The expression of the PYCR1 gene is increased in numerous malignancies and correlates with poor prognosis. PYCR1 expression sustains cancer cells’ proliferation and survival and several mechanisms have been implicated to explain its oncogenic role. It has been suggested that the biosynthesis of proline is key to sustain protein synthesis, support mitochondrial function and nucleotide biosynthesis. However, the links between proline metabolism and cancer remain ill-defined and are likely to be tissue specific. Here we use a combination of human dataset, human tissue and mouse models to show that the expression levels of the proline biosynthesis enzymes are significantly increased during colorectal tumorigenesis. Functionally, the expression of mitochondrial PYCRs is necessary for cancer cells’ survival and proliferation. However, the phenotypic consequences of PYCRs depletion could not be rescued by external supplementation with either proline or nucleotides. Overall, our data suggest that, despite the mechanisms underlying the role of proline metabolism incolorectal tumorigenesis remain elusive, targeting the proline biosynthesis pathway is a suitable approach for the development of novel anti-cancer therapies.

Two Variations and one Similarity in Memory Functions Deployed by Mice and Humans to Support Foraging

Spencer Talbot, Todor Gerdjikov, Carla De Lillo

Assessing variations in cognitive function between humans and animals is vital for understanding the idiosyncrasies of human cognition and for refining animal models of human brain function and disease. We determined memory functions deployed by mice and humans to support foraging with a search task acting as a test battery. Mice searched for food from the top of poles within an open arena. Poles were divided into groups based on visual cues and baited according to different schedules. White and black poles were baited in alternate trials. Striped poles were never baited. The requirement of the task was to find all baits in each trial. Mice's foraging efficiency, defined as the number of poles visited before all baits were retrieved, improved with practice. Mice learnt to avoid visiting unbaited poles across trials (long-term memory) and revisits to poles within each trial (working memory). Humans tested with a virtual reality version of the task outperformed mice in foraging efficiency, working memory, and exploitation of the temporal pattern of rewards across trials. Moreover, humans, but not mice, reduced the number of possible movement sequences used to search the set of poles. For these measures, interspecies differences were maintained throughout the 3 weeks of testing. By contrast, long-term memory for never-rewarded poles was similar in mice and humans after the first week of testing. These results indicate that human cognitive functions relying on archaic brain structures may be adequately modelled in mice. Conversely, modelling in mice fluid skills likely to have developed specifically in primates requires caution.

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