Summaries of 2017 research
Lay summaries of research that involved animals in 2017.
As part of the Concordat on Openness on Animal Research in the UK, we provide lay summaries of research that involves animals for all new granted project licences.
Molecular determinants of cortical development
What animals are you planning to use?
We will use mainly embryos and young animals from wild type and genetically altered (GA) mice.The GA animals are purchased from commercial suppliers or obtained through collaborations with other laboratories. We may generate some GA animals at Cardiff University.
For what purpose are the animals going to be used?
Our animals are part of different studies to help us understand how a particular brain region, the cerebral cortex, is formed during development. We want to gain insight into the four different processes that are necessary for the formation of the cerebral cortex, to better understand how alterations in these processes lead to brain disorders in infants or later in life. These four processes are: 1) neurogenesis, in which the neurons are generated by specific progenitors; 2) fate specification, a process by which neurons in the cortex acquire a particular identity that will determine their function and pattern of connectivity; 3) migration, a necessary step for the new born neurons to reach their final position within the cortex; and 4) circuit formation, when neurons identify their synaptic partners and establish contact with them.
What will be the harms to those animals and how will these be limited?
The procedures that will be used are not expected to cause severe harm to the animals. Some of them will be humanely killed to obtain tissue for our research and some of them will receive an injection before that. Other animals will undergo surgery. This is conducted under anaesthesia, following aseptic technique to ensure the maximum level of safety, and always using analgesia (pain relief). We will also assess some behavioural characteristics of the animals by observing them in different settings.
What alternatives did you consider before embarking on the use of animals in your research?
As the cerebral cortex develops, it receives cells from different parts of the brain and signals from varied sources. These cells and signals influence the processes that are necessary for the cortex to form: the generation of neurons, their migration to their final position within the cortex and the contacts that they establish, with other neurons in the cortex or in other brain regions. Because of this complexity, it has not been possible yet to create an in vitro model to study cortical development in the lab. However, we also use cell culture when we study basic mechanisms that do not depend so much on the complex arrangement of cells and signals of the in vivo cortex.
What will be the expected benefits?
The research proposed for this project comprises basic neurobiology but it could also eventually be relevant from a clinical point of view in the future. The expected results would translate into two potential benefits: - First, it will generate new knowledge about the function of several genes, involved in distinct processes during cortical development, contributing to our understanding of brain development and function. - Second, it will shed light on the pathophysiology of megalencephaly-polymicrogyria- polydactyly-hydrocephalus syndrome 3 (MPPH3), a human disorder caused by mutations in the CCND2 gene (one of the genes that we will study), and potentially of other disorders, providing information to affected families to help them understand the disease. A good understanding of the different molecules and processes involved in corticogenesis is also essential when new risks are identified that can severely affect the mental health of the population. An example is the current epidemic of Zika virus. This virus infects cortical progenitors very efficiently and has been linked to microcephaly, but new studies suggest that it might be causing further neurological problems that are only detected later in life.
Therapy resistance in blood cancer
What animals are you planning to use?
In the majority of cases we use adult wild-type mice. Only in rare cases of very specific and relevant scientific questions, we have the option to employ genetically altered mice. In these cases the genetic alteration is chosen based on previous scientific results and therefore respective mouse strains will not be created at Cardiff University but bought in from well trusted sources.
For what purpose are the animals going to be used?
Our animals are part of the overall strategy in the department to understand and to overcome mechanisms of therapy resistance in patients with highly malignant acute and chronic leukaemia. Therefore we model leukaemia in mice using techniques we have developed over many years.
What will be the harms to those animals and how will these be limited?
All measures will be taken to reduce adverse effects experienced by the animals to a minimum. The worse expected adverse side effect is that the animals develop a picture of leukaemia which may reach a moderate level of severity. Otherwise all treatments and interventions will result in no more than transient discomfort and no lasting harm.
What alternatives did you consider before embarking on the use of animals in your research?
Experiments in animals are undertaken only based on clear evidence from relevant cell and tissue culture in the lab. Unfortunately, some principles such as clonal evolution or stem cell capacity can only be proved using live animals, because no alternative in vitromodels are available.
What will be the expected benefits?
Our findings will increase our knowledge of the mechanisms of why leukaemia develops and will have important implications for understanding mechanisms of resistance in leukaemia. Furthermore it will contribute to answer the question of why in some groups of leukaemia patients current therapies do not have the desired curative effects seen in other patients. The long term aim of this project is to create the basis for a future design of specific therapieswhich are more precisely adapted to the individual patient.
Regulation of antiviral immune responses
What animals are you planning to use?
We will use mostly adult wild type and genetically-altered mice (not created in Cardiff).
For what purpose are the animals going to be used?
Our studies aim to help understand: 1) how inflammation produced by the human body in response to viruses can be treated, 2) how cells of the immune system can be harnessed to improve infection control and 3) how the immune response can be manipulated to improve how the body reacts to virus-based vaccines.
What will be the harms to those animals and how will these be limited?
To study viral infections requires us to infect mice with viruses such as influenza. Thus, animals used in these experiments will often be infected with viruses, causing mild illness and weight loss that will be monitored closely throughout infection. Pilot experiments are performed to ensure that the lowest possible virus dose (which thus induces the least disease) is used.
What alternatives did you consider before embarking on the use of animals in your research?
Wherever possible, studies are performed using cells in the laboratory that are infected with virus, or studying immune responses in blood of human volunteers.
What will be the expected benefits?
Findings from these studies will assist 1) the design of medicines to treat damage in the body that is triggered by viruses and 2) immunization strategies that use safe versions of viruses as part of the vaccine.
Arthritis pathology and the impact of therapy
What animals are you planning to use?
Wild type mice and rats and genetically altered mice generated externally.
For what purpose are the animals going to be used?
Our animals are part of a study to help us understand how the immune system contributes to the development and progression of inflammatory arthritis (e.g. rheumatoid arthritis).
What will be the harms to those animals and how will these be limited?
Animals are injected with agents that cause arthritis with features similar to human disease. Animals are handled by trained and experienced researchers and are monitored closely for clinical signs of arthritis and indicators of wellbeing (e.g., appearance, behaviour and weight). To minimise suffering during injections, mice are anaesthetised and arthritic mice are handled on soft surfaces. Animals remain mobile and continue to feed and drink. Our genetically altered mice do not develop harmful characteristics.
What alternatives did you consider before embarking on the use of animals in your research?
Our animal studies are based on clinical observations generated using patient samples. This ensures our research addresses questions relevant to human disease. Our animal studies are supported by in silico and cell culture approaches that define mechanisms that promote arthritis progression. Animals are necessary to study the complex communication networks that occur between immune cells and joint tissues during arthritis.
What will be the expected benefits?
We aim to identify mechanisms that explain why patients develop inflammatory arthritis, and why some patients respond well to current drugs (e.g., anti-TNF) while others do not. By exploiting immunological mechanisms that underpin arthritis progression we aim to develop new drugs for patient treatment. Also, identifying biomarkers that can inform the best drugs for patients on an individual basis will aid a personalised approach to arthritis treatment.
Investigating dendritic and synaptic structure function relationships in neuropsychiatric disorders
What animals are you planning to use?
We will use wildtype and genetically altered mice and rats of all ages.
For what purpose are the animals going to be used?
Our animals are part of a series of studies that will help us to understand the structure and function of specialised brain cells, known as neurons, and the connections between them, called synapses, which allow the brain to process sensory information and are responsible for behaviours including attention and sleep. We use brain tissue harvested from humanely killed rodents to measure electrical activity and intracellular signalling mechanisms (calcium) in structures known as dendrites. Dendrites are the specialised structures on neurons that receive and interpret incoming chemical signals from other cells and their function is critical for the processing of information in the brain. By gaining a better understanding of dendrites, neurons and circuits in the brain and how they regulate behaviour we can better understand how their disruption might lead to neurological disorders including schizophrenia, autism spectrum disorder and epilepsy. We work with animals that have been genetically modified to change the expression of specific genes that have been linked in human genetic studies to particular diseases. Using this approach we seek to identify the function of specific disease risk genes on neuronal and brain function and identify potential new targets for therapeutic manipulation.
What will be the harms to those animals and how will these be limited?
Some animals in this project will undergo surgery to allow us to inject viruses into the brain that allow us to experimentally manipulate brain circuits. These surgeries are considered relatively minor procedures and are carried out under aseptic conditions by fully trained and competent individuals. All animals are provided with appropriate anaesthetic, antibiotic, anti-inflammatory and analgesic medications as required based on advice provided by a trained and licenced veterinary surgeon. Animals from which tissue is harvested for electrical recordings are humanely killed using an overdose of anaesthesia.
What alternatives did you consider before embarking on the use of animals in your research?
The complex circuitry of the brain limits the alternative options for studying particular aspects of the structure and function of its cells and circuits. However, alongside the animals used in the projects described we also use stem cell derived neurons which are taken from human volunteers and grown in cell culture and computational models.
What will be the expected benefits?
The work we are undertaking in this project aims to generate a new understanding of the function of key neurons and circuits in the brain and will provide a greater understanding of human genes linked to the human disease that produces the behavioural symptoms observed. By understanding how deficits in dendritic and synaptic function disrupt the function of neuronal networks we hope to be able to identify and test new target sites for therapeutic intervention using novel pharmacological or cell based therapies.
Mechanism of absence seizures
What animals are you planning to use?
Juvenile and adult rats and mice, some with spontaneous gene mutations.
For what purpose are the animals going to be used?
Our animals are part of a study to understand the mechanism underlying the expression of absence seizures in children and teenagers. These are non-convulsive seizures that consist of sudden, relatively brief lapses of consciousness accompanied by simultaneous activity of many neurons. These seizures are often accompanied by additional complications, including attention deficits, depression and anxiety that are not controlled by the drugs that block the seizures.
What will be the harms to those animals and how will these be limited?
The procedures involve only minor and temporary distress to the animals, including brief surgery under full anaesthesia, injection of antibiotics and anti-inflammatory drugs and temporary removal from the home cage. All animals are provided with the appropriate pain relief.
What alternatives did you consider before embarking on the use of animals in your research?
Artificially kept cells and neurons, and computer programs that simulate the electrical activity of brain cells. None of them, unfortunately reproduce the connections among nerve cells that are characteristics of the intact nervous tissue. For this reason it is important to study the whole animal.
What will be the expected benefits?
Current medications, given as monotherapy, suppress absence seizures only in 50% of children and teenagers suffering from absence seizures. Our study should identify aberrant proteins that could be targeted for the development of novel drugs, in order to help children and teenagers with absence seizures.
Lay summaries by year
Consideration of the 3Rs is the basis of everything we do related to animal research.