Modern biology is becoming more and more multidisciplinary. This is especially the case for the area of 'Systems Biology', which aims to predict how the different biological processes interact to result in a functional organism. These processes include the transcription of DNA into RNA, which codes for amino acids that make up the proteins, as well as the levels of hormones and metabolites that affect the biological processes. In the proposed network, we address how variation at the DNA level affects the transcription of DNA into RNA and how this then affects the characteristics of the whole organism. The aim is to reconstruct the networks that describe how genes interact. While conceptually straightforward, the area of research requires integration between biology, computer science (bioinformatics) and mathematics. At present, there is already some level of integration between researchers in these areas, but a lot of work is done in isolation. In the proposed network we will bring together: 1) biological research in plants, animals and humans. 2) Bioinformatics research which covers databases that contain known information on gene networks but also translates novel statistical and mathematical models into user-friendly software. 3) Mathematical biology, focussed on the methods of reverse-engineering of gene regulatory network, from a variety of experiments. The network will achieve its goal of further integration by organising annual meetings. These meetings will consist of an interactive workshop followed by a scientific conference. The workshop will provide ample opportunity for training of young researchers, dissemination of 'best practise' and new software tools and initiation of new collaborative research. The Conference will disseminate the cutting edge of the research area to the wider community.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Restricted blood flow/oxygen to the brain occurs during the birth of 2-3 babies per 1000 in the UK and depending on the severity, can result in permanent, life-long brain injury including cerebral palsy. The emotional, social and financial burdens to the children and their families is considerable and our work focuses on developing therapies to ameliorate the consequences of this devastating injury. Following initial injury during birth, there is a delay of a few hours before the majority of brain cell death occurs and this delay provides clinicians with a valuable treatment window. Currently the only available treatment is therapeutic hypothermia, in which the body temperature of the baby lowered for three days. When hypothermia is initiated rapidly after birth, it can double the chances of survival without brain injury. Unfortunately, it is only successful for 1 in 7 neonates, but it proves that we can intervene with therapy following injury and still produce an effective outcome. This is critical because as yet we cannot predict in advance which babies will suffer brain injury. Mitochondria reside inside all cells in the body (except red blood cells), and function to generate cellular energy needed for survival. Brain injury and brain cell death occurs when cellular energy falls to extremely low levels. Therefore, although many events are triggered after the insult, we believe that mitochondria act as a hub where all these events converge. Following the initial insult, the outer mitochondrial membrane becomes leaky, releasing mitochondrial contents into the cell and in doing so, committing the cell to death. At the same time, the inner mitochondrial membrane becomes disrupted, freeing pro-death molecules normally held securely within the folds of the inner membrane. OPA1 is a mitochondrial protein which acts as a "molecular staple" holding together the folds of the inner mitochondrial membrane. Data from our animal model shows that unfortunately, OPA1 becomes degraded after the birth injury. We predict that if we protect the integrity of OPA1, we will provide mitochondria with additional defences to resist releasing pro-death molecules, and continue to feed the cell with the energy it needs to stay alive. We will perform research in our animal model and in a variety of cultured brain cells to evaluate the impact of OPA1 degeneration on brain injury. We will also identify new mechanisms which might contribute to the degradation of OPA1, thus providing novel targets for future drug development. Finally we have the opportunity to use mitochondrial biology to develop a new, non-invasive and early detection method to identify how severely an infant's brain has been injured. By taking this combination of approaches, we aim not only to increase our knowledge of OPA1 biology, but also to use it to our advantage in developing drugs and new tools to improve the outcome of babies at risk of developing lifelong neurological impairment.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

After fertilization, a single zygote proceeds through a series of cleavage steps to develop into a multicellular embryo, called a blastocyst. The cells of the blastocyst are capable of generating all adult cell types, a phenomenon known as pluripotency. The inner cell mass (ICM) of the blastocyst can moreover be cultured in a dish as pluripotent embryonic stem cells (ESCs). ESCs have become invaluable tools in regenerative medicine and to study development itself. With 1 in 8 couples experiencing infertility in the UK, it is ever more important to understand the factors contributing to healthy embryo development. Transposable elements (TEs) are parts of our DNA that are currently or historically mobile, -i.e. having the capacity to 'paste' themselves into new places in the genome. Many TE sequences used to be thought of as simply 'junk DNA'; however, we are beginning to understand that TEs have evolved to play new and unexpected roles in development and disease. For example, uncontrolled TE activity has been implicated in neurodegeneration and cancer. However, the expression of many TEs is also high in normal development, suggesting that they may also have beneficial roles in cells. This proposal focuses on exploring the function and regulation of a particular TE, called mouse endogenous retrovirus type L, MERVL. MERVL is the earliest expressed TE, and is transiently upregulated in mouse embryos at the 2-cell stage. This stage, conserved in human in 4-8 cell embryos, encompasses an essential process called Zygotic Genome Activation, when the embryo begins to turn on its own genes for the first time. These embryos are also considered "totipotent", meaning that they can not only generate embryonic tissues but also extra-embryonic tissues (like placenta). Interestingly, a small proportion of ESCs transiently become "2C-like" in normal culture, also possessing enhanced developmental potency. Here, we will use mouse ESCs and mouse embryos to investigate how and why MERVL regulation is important in early development. Using these tools, we will identify and characterize key factors required to activate and repress MERVL. In turn, we will investigate how these factors regulate the 2-cell stage, and affect ZGA and totipotency. To understand how MERVL and other TEs are directly regulated, we will combine genome-editing systems, called CRISPR/Cas9, with recent biochemical tools to pull out sets of proteins that bind MERVL. Lastly, we will explore the conservation of MERVL function and regulation in human cells, where a similar TE, HERVL, is known to play a conserved role. We aim to a) understand how HERVL regulates the 4-8 cell stage and human ZGA b) investigate how new HERVL regulators might contribute to specific cases of disease. These studies will significantly increase our understanding of how TEs contribute to early development, and will shed insight on how such processes are perturbed in disease.