Chronic Obstructive Pulmonary disease (or emphysema and chronic bronchitis) is a family of lung diseases usually but not always caused by cigarette smoking. There is an urgent need to develop new drugs to treat this condition since existing therapies are insufficiently effective. Importantly in more advanced disease complications outside the lung become as important as the lung disease itself and in fact one of the most effective treatments, pulmonary rehabilitation (supervised exercise training) is thought to work in large part by improving the strength and function of the walking muscles; thus we believe a drug which could magnify or extend the benefit of this treatment would be every useful. Thus the aim of this work package is to bring together the groups interested this field in Great Britain with selected drug companies. Three stages of the WP are described. In the first we will assess what material is available and whether, by sharing, the consortium can achieve some ?quick wins? which will facilitate the development of drugs or ideas already known to the participants. In the second we will do some detailed studies which will relate actual rates of protein synthesis in the leg muscles to more readily accessible measures that can be obtained from blood or muscle since this will allow the latter measures to guide drug development more reliably. As part of this work we will also build the largest ever cohort of COPD patients from whom a muscle biopsy and clinical data are available. Lastly we will study patients around the time of rehabilitation (which improves muscle function) and acute exacerbation (which worsens it) to try to identify further targets for new drugs

Optical coherence tomography (OCT) is a 3D high-resolution optical imaging technology. It is widely used for imaging internal structures of the eye and is also finding a range of other medical applications such as in dermatology and cardiology. It differs from conventional microscopy in that interferometry, together with a broadband or tunable optical source, is used to achieve optical sectioning. Through optical sectioning, and the intrinsic rejection of multiply-scattered light, OCT imaging is able to penetrate 1 to 2 mm inside scattering tissue, allowing 3D volumetric imaging. Using Fourier domain OCT techniques entire volumes can be collected, reconstructed and displayed in seconds. Endoscopic OCT brings the high-resolution volumetric imaging capabilities of OCT to the interior of the body, opening up new possibilities for minimally-invasive diagnosis and interventional monitoring. Most endoscopic OCT systems work in a side-viewing configuration, where images are acquired radially outwards from the OCT probe, similar in appearance to endoscopic ultrasound. This works well for imaging narrow, tube-like structures (such blood vessels and parts of the gastrointestinal tract), but it is not ideal for areas such as the ear, nose and throat (ENT), for the upper airways, or for general surgical guidance. These applications would benefit from a probe that is forward looking; effectively an endoscope which produces high resolution en-face images or volumes from beneath the tissue surface. However, forward-viewing OCT endoscopes are challenging to build with current technology as they require a two-dimensional fibre scanning mechanism to be built into the probe head; this scanning is typically either bulky, slow, or limited in scanning range, and leads to complex devices. This project, for the first time, proposes and evaluates solutions which add depth-resolving capabilities to en-face viewing endoscopes without a miniaturised scanner. The research will explore a new approach for distal control of scattering and interference which is amenable to miniaturisation in the form of an adapter which could be fitted to a fibre imaging bundle or a miniature camera. The investigators have recently patented an approach for such a miniature adapter that makes use of a technique called full-field swept source OCT, where multiple images are captured, each at a different illumination wavelength, and processed to recover the OCT volume. To date there has been no report of good quality depth resolved imaging via a fibre bundle, and so if successful this project will represent a significant advance in the field of fibre bundle imaging. The aims of the project are to demonstrate that the approach is a feasible and practical route to developing compact forward-viewing OCT probes with clinical utility. The earlier stages of the project involve developing a full understanding of the new technology. In parallel, a design will be developed for miniaturisation in collaboration with clinical partners advising on the design requirements. Packaged prototypes will then be developed, characterised and validated using a range of phantoms and tissue samples. In parallel with validation studies on the core probe design, additional scientific avenues will be pursued, including to combine the probe with other imaging modalities such as fluorescence. The project will build on 25 years of experience of building OCT instrumentation in the Applied Optics Group at the University of Kent, as well as achievements in developing endoscopic microscopes and OCT probes and performing coherent imaging though fibre bundles. Industrial partners will provide expertise in miniaturised fibre optic components, compact probe packaging, and miniature cameras, while clinical partners from major hospitals will provide advice and support in developing the probe towards practical clinical applications in ear, nose and throat and the upper airways of the lungs.

The heart works as a muscular pump, which needs a healthy amount of shortening and lengthening of heart muscle in each region of the heart to maintain good overall pump function. Diseases such as heart attacks, heart failure and heart rhythm disorders, as well as heart damage caused by cancer therapy drugs, are diagnosed and monitored by measuring pump function, including changes in regional heart contraction and motion. Strain is an engineering quantity which measures contraction and relaxation as a relative change in length. Accurate measurement of strain in all regions of the heart is vital to understand mechanisms of disease. Medical imaging methods such as echocardiography and cardiac magnetic resonance imaging are being used to measure regional strain, to help diagnose disease and monitor treatment, and to develop and evaluate computational analyses of heart function. However, current quantification methods are inaccurate and imprecise, since strain is highly sensitive to image artefacts, noise, and low resolution. Worse, strain estimates vary systematically between different imaging modalities and even between different commercial software products. Vendors use "black box" closed source solutions which hamper reproducibility. This leads to different standards and measures being used by different doctors. Subsequently, it is not known which of the many measures available is best for diagnosing heart disease and predicting outcomes. Clearly, a new way of solving this problem is required. This project will develop novel technologies for measuring motion and strain in the heart which are standardized between imaging modalities. We will use "artificial intelligence" neural network methods to automatically process different types of medical imaging examinations to obtain more accurate and precise strain measurements. These networks will be trained to learn how to predict the underlying motion and strain from thousands of image simulations, as well as thousands of patient scans, using a statistical atlas of heart motions. By simulating realistic images with exact high resolution heart motions derived from the statistical atlas, the networks will learn how to handle image artefacts, noise and low resolution in real images. More fundamentally, we will examine how statistical atlasing methods can help us discover which strain measures are best for diagnosing and predicting heart disease. We will then deploy these methods in high-throughput heart imaging clinics at St Thomas' Hospital, Royal Brompton Hospital, and other NHS hospitals. By making open-source tools widely available for doctors, we will test how standardised measurements and reports will work in practice. This will also reduce the costs of patient evaluation, by getting the information we need from commonly-performed scans and avoiding the need for specialized equipment. More accurate and precise evaluation of patients with heart disease will improve patient care, by identifying high risk patients and optimizing treatment dose. In particular, many cancer patients suffer from heart muscle damage caused by their cancer drug therapy. Our tools will enable better identification of which patients are at most risk and may require a change of treatment.

Reproductive success is crucial for the preservation of species and sustainable agriculture and food, in addition to being essential to human health. In human populations, poor sperm quality is a noteworthy vulnerability that explains around half of infertility cases but remains very little understood. In this study we propose to study the fundamental basis of male factor fertility in order to shed fresh light in this research area. We propose that there is a major but overlooked role of male-specific motile cilia in the production of healthy, fertile sperm. This proposal is focussed on characterizing new genetic factors in male fertility and exploring the balance of sperm and cilia requirements to develop and release healthy male reproductive cells (gametes). Cilia are hair-like organelles extending outside a cell and motile cilia are required in certain specialised areas of the body, for example in our airways beating of cilia lining the lung and upper airways are responsible for mucus flow and pathogen removal. The role of motile cilia in efferent ducts that are unique to male humans, is poorly understood. The efferent ducts are tubules that allow sperm made in the testis to be released into the ejaculatory duct via a structure called the epididymis. Sperm develop in the testis and are transported through the efferent ducts and epididymis, where they undergo maturation as they proceed, with growth of the sperm tail (flagella) giving them motility. Only after this transport do the sperm reach their full fertilizing capacity. In the testis (seminiferous tubules), male germ cells undergo several steps to become highly specialized spermatozoa. This process requires precisely timed gene expression and correct protein function in order to produce fertile sperm and ensure reproductive success. Malfunction of proteins at any time point during this process results in compromised sperm development. Therefore, we aim to characterize the function of genes identified in genetic screens of infertile male patients, using fly as a model organism because spermatogenesis is a conserved process with similar genes coding for proteins in fly and man. Our experiments will help us to define the link between genetics and male fertility in evolutionary conserved processes. The last phase of spermatogenesis involves formation of the sperm tail. The core structure of the motile cilia and sperm tail is almost identical, but with recently identified protein differences. These differences will be elucidated and the effect of specific genetic mutations on male fertility through sperm tail and/or efferent duct cilia functions characterized. To do this, we will examine the sperm quality and structure in patients a disease caused by mutations of the motile cilia in airways, as they have high male fertility that is not well characterised yet. The motility pattern of different cilia types (airway, efferent duct) and sperm are different and therefore we hypothesize that their motility producing complexes also differ. We will investigate motility-producing dynein composition and assembly, in sperm from humans with cilia mutations and in efferent duct cilia from mice with cilia mutations. We speculate that efferent duct cilia may interact with sperm through molecules they release in special packets (vesicles) and we aim to investigate the presence and role of this crosstalk in mouse mutants where the cilia specific protein transport is inhibited. Furthermore, we will develop a cell culture model to study the importance of cilia motility and other characteristics to better explore their role in production of fertile sperm. Overall, these experiments aim to clarify the molecular mechanisms underlying cilia related fertility and identify the influences of cilia versus sperm related mechanisms in successful sperm development in mammals.

Chronic Obstructive Pulmonary Disease (COPD) is a very common lung disease that is usually smoking-related. People with COPD are often breathless, particularly when exerting themselves. COPD is responsible for over 25,000 deaths in the UK annually and is predicted by 2020 to be the third leading cause of death and the fifth leading cause of disability worldwide. Currently it is very difficult to objectively assess disease severity as there are many aspects to the condition that influence patients? symptoms, some of which are not focused on the lungs. Traditionally, the amount of air you can blow out in one second (FEV1) has been used to assess severity in COPD. Regulatory authorities use an improvement in FEV1 to make decisions about the approval of new drugs for COPD. However FEV1 is relevant to only some of the processes involved and hence over-reliance on this measurement would bias against treatments where the main action is outside the lungs. In healthy older people, usual walking speed predicts loss of independence, falls, nursing home admissions, dementia and death, and is very easily measured. Walking speed may slow due to lung function decline, muscle weakness, breathlessness, the presence of multiple medical problems, poor balance, low mood and cognitive decline ? all factors seen in COPD, and it may be a simple but global marker of disease progress. The proposed research study aims to assess whether usual walking speed is a useful marker of disease severity in COPD, whether it relates to measures of exercise capacity and whether it has value in predicting hospital admission and death in patients with COPD. The research should be of interest to all health care workers involved in the care of COPD patients as it will validate a simple test that could easily be introduced into clinical practice. This research should also be of interest to the pharmaceutical industry as it could help guide the development and assessment of new and more effective medicines for COPD.