Our work will help to understand why disease develops and to find new ways to diagnose, prevent and treat a range of illnesses − such as cancer, heart disease, stroke, infections and neurodegenerative diseases. We will bring together outstanding scientists from all disciplines, carrying out research that will help improve the health and quality of people's lives, and keeping the UK at the forefront of medical innovation.

Growth of the brain is often prioritized or spared over that of other fetal organs during intrauterine growth restriction (IUGR). This brain sparing is thought to be essential for fetal survival but it is also associated with postnatal neurodevelopmental defects and adult dysmyelination. Despite its importance, the cellular and molecular mechanisms linking fetal brain sparing to long-term alterations in the myelin-producing glia, oligodendrocytes (OLs), remain unclear. Using a mouse model of IUGR, my preliminary data identify a specific developmental delay in the onset of OL differentiation at fetal/neonatal stages. Surprisingly, this early delay becomes over-compensated at postnatal stages, with supernumerary pre-myelinating OLs (Pre-OLs) and a Pre-OL-to-OL imbalance correlating with an adult neocortical myelin deficit. The overarching goal of this proposal is to identify the cellular and molecular mechanisms by which IUGR changes the life-long development and function of the OL-lineage. To achieve this, I will combine malnutrition and placental deficiency models of IUGR in mice with transgenic methods, advanced imaging, single-nucleus transcriptomics and metabolomics. This mouse project will deliver a mechanistic understanding of the developmental origins of dysmyelination and provide useful new insights for future human studies of dysmyelination-associated neurodevelopmental disorders.

Most studies treat Down syndrome (DS) as a single entity. Our novel aim is to focus on individual differences and subgroups at the cellular, genetic and cognitive levels to explain why the DS phenotype varies so much. For example, despite all DS individuals presenting with Alzheimer's Disease pathology, only a subgroup develops dementia. Is this due to cellular, molecular, genetic and/or cognitive differences? Can we identify these differences not only in adulthood, but also in infancy? If so, early diagnosis and intervention can be targeted. To study DS cognition longitudinally, we will develop comparable assessments for DS infants, adults and mouse models, to characterise deficits associated with hippocampal, cerebellar and frontal regions. Uniquely, we will correlate cognitive/genetic profiles with defects in neurogenesis, neurite/synapse plasticity, mitochondrial dysfunction, A-beta accumulation within participants neurons, differentiated from iPSC. We will create a Biobank and genotype/phenotype database as platforms for add-on pharmacologic/metabolomic/imaging projects, and clinical trials. This project aligns methods with other DS studies globally, but is unique in encompassing different age cohorts, integrating human cognitive development, ageing, neurobiology, genetics, cellular and mouse modelling. It is strategic for improved health, and timely, as therapies for DS cognitive deficits and decline are now realistic. Down Syndrome (DS) is the most common condition involving learning disability, and arises because people have an extra copy of chromosome number 21. This proposal is for cutting-edge inter-disciplinary research by leading geneticists, psychiatrists and neuroscientists to understand how learning disabilities develop in people with DS and to identify the processes involved in the decline that often occurs as people with DS age. We will link with US and European colleagues to develop similar asses sments for babies and adults with DS. We will particularly focus on individual differences and sub-groups in DS to understand for example why some go on to develop dementia. Participants will be asked for sputum or blood tests and hair samples for genetic analyses to identify the genes involved in DS learning and ageing. We will also study cultured cells from DS people to examine related processes. We will link this work with studying similar functions in specially created mice to help us unders tand the biology of DS. This research will reveal how genes influence brain functions throughout life in people with DS and will lead, we hope, to treatments to prevent decline and improve brain function, which can be tested in clinical trials.

Do we have sufficient understanding to engineer bespoke neural tissue? To test this, we will use the developing neural tissue to establish a synthetic approach to form robust patterns of cellular organisation. This will test and extend our understanding of neural tube development and create tools to control and engineer tissue for use in synthetic applications and disease modelling. Previously we: - Developed quantitative understanding of the genomic, molecular and cellular mechanisms of neural tube development. - Established methods for the biomimetic generation of neural tissue from Embryonic Stem Cells (ESCs). - Established collaborations with physicists and computer scientists to develop data driven dynamical models. On these foundations we will develop a system for precision tissue engineering based on ESCs, re-engineered neural tube components, and multiscale models. We will: - Establish optogenetic control of extracellular signals to instruct spatial- temporal pattern formation in synthetic ESC derived neural tissue. - Generate a suite of synthetic gene regulatory elements with defined regulatory function and use these to produce novel circuits that elicit predictable responses. - Combine extracellular and intracellular modules to produce precision programmable synthetic developmental patterns of gene expression and cell fate. To guide experiments and interpret data, we will use computational simulations constrained by quantitative experimental measurements.

Our work will help to understand why disease develops and to find new ways to diagnose, prevent and treat a range of illnesses − such as cancer, heart disease, stroke, infections and neurodegenerative diseases. We will bring together outstanding scientists from all disciplines, carrying out research that will help improve the health and quality of people's lives, and keeping the UK at the forefront of medical innovation.