Cell movements play a central role throughout vertebrate embryogenesis. Migration is as fundamental a feature in proper development as proliferation, differentiation, and apoptosis. Yet less is known about cell migration patterns and the molecular mechanisms that govern them then about other aspects of development. By nature, the study of cell migration requires combined knowledge of anatomical landmarks and dynamic migratory patterns. An understanding of such dynamic processes is essential to integrate our increasingly detailed knowledge of genetic regulatory networks into the context of cellular interactions and morphogenesis. Recent technological advances have opened up an exciting new era in developmental biology where we can now address in detail and in real-time how cell behaviour governs the development of the embryo. Our groups are examining such intricately choreographed processes in distinct yet overlapping systems, such as the early mammalian embryo and in the mid-gestation to adult vertebrate nervous system. In order to be able to investigate such cell behaviour in the 3-dimensional context of the organism, we require a microscope with the ability to optically section our samples and obtain high resolution images. Furthermore we require a microscope that can do this over time, as development occurs over time. The state-of-the art equipment requested in this proposal would fulfill these requirements and enable us to achieve our objectives which address fundamental questions about the development of the adult form.

Birth defects, cancer, regeneration and degeneration are all processes that can be better understood by the study of normal development of embryos. Recent advances in the field have shifted the focus from individual genes to complex regulatory cascades that operate in diverse sub-cellular compartments, between cells and between tissues. This, in turn, requires the study of the distribution of gene products (proteins) and their biological effects at a very fine scale: the scale of individual cells and even within cells. Fortunately, this is facilitated by new types of microscope. The one being requested in this application is a confocal laser scanning microscope that, by illuminating only one tiny spot at a time within a specimen (but scanning the illuminating laser beam progressively across and through it), eliminates most of the glare and fuzz of conventional microscopes. Such instruments enable images from deep within tissues to be gathered and different colours that identify different proteins to be detected simultaneously. The department requesting this instrument does not have its own confocal microscope, and several members of the department currently have to go to remote sites to collect these crucial images. The provision of the requested instrument will thus result in greatly increased efficiency in using Research Council and other funds for project work.

In animals, cells need to move during development and in response to infection or tissue damage. Cell movement is driven by the cytoskeleton, principally by filaments made of actin molecules, and also requires changes in the way cells attach to other cells or to molecules around them. We want to understand more about how proteins inside cells drive or inhibit cell movement, and therefore be able to more effectively use these proteins as targets for drug therapy against several diseases including chronic inflammatory disorders, heart disease, Alzheimer's and some cancers.

The leishmaniasis are parasitic diseases caused by one of several species of single cell parasites (Leishmania) that are transmitted to humans by the bite of infected phlebotamine sand flies. These diseases affect over 150 million people across 98 countries worldwide, including many low and middle income countries (LMICs). Some forms of leishmaniasis are fatal, whereas other are very stigmatising and affect quality of life, particularly in children and women. Few drugs are available for patients leishmaniasis and no vaccines are currently registered for use in preventing or treating these diseases. Importantly, the drugs that we do have are not universally effective and often have significant side effects. Sometimes patients even in the same geographical area will respond quite differently to therapy, and for some drugs effectiveness may vary widely between different countries. In order to make the best use of current and future drugs for the leishmaniasis, we need to understand more about why this is the case, and use that information to select appropriate drugs or drug combination for use in different settings. Using the appropriate treatment would save costs in health care, minimise the patient suffering that results from administering ineffective treatments, and reduce the economic burden of disease on patients, their families and communities. In this proposal, we are aiming to lay the foundation blocks that will drive a new way of managing patients with leishmaniasis and conducting research into these diseases. We will use new molecular approaches to extract as much information as possible from small tissue samples that are collected from patients to diagnose their leishmaniasis, and use this information to start to develop new tests that can help clinicians decide on the best course of treatment. We will use the internet to ensure that the information obtained from these tissue samples is used most effectively for research, clinical decision making and for education and training. We will conduct an analysis of the added value of these changes in approach, in order to provide a case for their adoption by health systems in LMICs and by the funders of research. Ultimately, by adopting these practices we will seek to deliver improvements in health and economic prosperity in LMICs. The research we propose over the next two years will not provide all the answers, but will provide necessary proof of concept data to support applications for future funding that may allow us to realise this longer term ambition.

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.