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.

Doctoral Training Partnerships: a range of postgraduate training is funded by the Research Councils. For information on current funding routes, see the common terminology at https://www.ukri.org/apply-for-funding/how-we-fund-studentships/. Training grants may be to one organisation or to a consortia of research organisations. This portal will show the lead organisation only.

Skeletal muscle is the largest and one of the most important tissues in the body. Not only does it perform obvious functions in allowing us to move and perform all the necessary physical tasks of daily living, it also has numerous other vital functions which are fundamental to health. These include being the most important source for the uptake of glucose in the body. However, there are numerous conditions where muscle loss occurs and "quality" declines, with the accumulation of intramuscular fat and fibrosis impairing both contractile and metabolic function. This occurs particularly in the muscles of frail elderly people. Given the fact that people are now living longer, this is resulting in a dramatically increasing population of people affected. Furthermore, there are also numerous diseases such as obesity and type 2 diabetes, as well a range of muscular diseases where fibro-fatty accumulation occurs. However, despite the prevalence the basic biological processes that influence these changes remain unclear. We have recently demonstrated that a population of cells resident within human skeletal muscle, called "fibroblasts" (which give rise to fibrosis), are also the cells that have the capability of giving rise to fat cells and fatty deposits.. The work outlined in this application is targeted at uncovering the molecular mechanisms which drive the process of a fibroblast to become a fat cell, in order to try to prevent or ameliorate fibro-fatty accumulation. With the combined expertise of biomedical researchers at King's College London and GSK, our collaborating industrial partner, we specifically aim to identify the molecules that initiate the events that cause a fibroblast to change into a fat cell; to chart the events that underlie the waning of the fibroblast characteristics and the waxing of those events that produce a fat cell; determine if the fibroblasts are viable and give rise to fat cells in vivo; and show that if you ablate the fibroblasts in skeletal muscle whether this prevents or impairs the fatty accumulation. To achieve these aims this grant brings together state-of-the-art techniques in human cell culture, cell imaging, RNAdeep sequencing, and in vivo work. It is a multidisciplinary collaboration of expertise in muscle biology at King's College with GlaxoSmithKline who have a parallel research programme targeted at muscle ageing and regeneration. The results of these experiments promise new insights into the mechanisms driving cell fate in skeletal muscle and have the potential to form the basis of new therapeutic agents directed at preventing fibro-fatty replacement in muscle.

The Grand Challenge is the treatment of brain diseases. Brain diseases span pain, sleep disorders, schizophrenia, mood disorders and neurodegenerative conditions. At any time 450 million persons worldwide are living with mental, neurological or behavioural illnesses and 24 million people worldwide suffer from dementias. The treatment of brain diseases is hampered by the blood brain barrier (BBB), a barrier between the blood and the brain which does not permit the passage of most drug molecules, due to the tightness of the intercellular capillary junctions, low uptake activity of capillary cells and the activity of efflux transporters. Previous attempts to target drugs to the brain and cross the BBB have involved the use of targeting ligands, e.g. mouse monoclonal antibodies for carrier mediated uptake or the inhibition of the above mentioned efflux transporters. However all of the particulate-based strategies (including the use of mouse monoclonal antibodies) that have been investigated over the last two decades have yet to yield any clinical products and the inhibition of the high capacity efflux transporters, which incidentally are not merely confined to the BBB, is not a viable clinical option. Our multidisciplinary consortium drawn from academia and industry (GSK) propose a new nanoscience based strategy founded on two recent significant findings: a) chitosan amphiphile based nanoparticles significantly increase the central activity of hydrophobic and peptides drugs via the intravenous and crucially oral routes, b) apolipoprotein E targeted nanoparticles bypass the brain capillary efflux transporters and cross the BBB, increasing drug delivery to the brain. The project aims to use these data to create an optimised nanotechnology brain delivery platform for peptides and low molecular weight drugs with low brain permeability. These drug classes represent the bulk of the compounds which are trapped in the drug development bottleneck due to: a) their poor brain exposure and b) the absence of suitable brain targeting strategies. Candidate drugs to be used are potential treatments for schizophrenia, pain and sleep disorders. These compounds and their potential indications are particularly relevant to the call (targeting psychiatric diseases) and a specific output of the project is a candidate medicine for the treatment of psychiatric or neurological disorders. The project will involve a significant level of particle engineering, where particle matrix chemistry, surface chemistry (including the discovery and evaluation of other BBB targeting peptides) and particle size will be systematically varied and the impact of these variations tested using in vitro and animal models. The resulting pharmacokinetic, pharmacodynamic and mechanistic data will inform the optimisation of the platform which is the ultimate goal of the project. Fundamentally the mechanism of brain permeation of the drug cargoes will be studied and elucidated en route to the optimised nanosystem and this will also fulfil a requirement of regulators and health providers, who desire an underlying mechanistic basis for new health technologies. Stage 2 of the project (GSK fully supported) will focus on the development of a clinical medicine based on the nanotechnology platform.Public engagement activities will occur via our nanomedicines.org website and also via public communication of science events. The key beneficiaries of the project will be patients, carers and the pharmaceutical industry as the platform will pave the way for novel therapeutic targets to be exploited. The engagement of scientists, with a past history of collaboration and a strong track record in nanoscience innovation, therapeutic target discovery, lead identification, drug targeting, translating scientific concepts to clinical products and basic brain physiology makes the consortium ideally suited to deliver the nanoscience based drug targeting goals of the Grand Challenge.

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.