Dr Martin Bootman

Recent genomic and histopathological analyses have shown that up to 17% of castration-resistant prostate adenocarcinomas (PCas) develop neuroendocrine (NE) features [1]. This trans-differentiation induces complete androgen-independence and promotes metastatic spreading. NE-PCas are currently incurable and associated with a dismal prognosis (median survival shorter than 1 year). Therefore, there is a dire need for the identification of effective therapeutic targets for this aggressive malignancy. Calcium dynamics govern key aspects of cellular phenotypes, including tissue specification, motility and proliferation. Notably, calcium-dependent alterations are reversible and targetable by small molecule inhibitors. Increasing evidence suggests that the alteration of calcium dynamics affects the initiation and progression of some malignancies. For example, we have shown that T-type calcium channels drive the proliferation of castration-resistant PCa [2]. However, the calcium signalling toolkit is organised in a complex network of interacting molecules. This interactome has never been explored systematically in the context of a specific malignancy. In this project, we propose to study the role of calcium-dependent genes in NE-PCa pathogenesis, with the ultimate goal of identifying new therapeutic targets.

Recent genomic and histopathological analyses have shown that up to 17% of castration-resistant prostate adenocarcinomas (PCas) develop neuroendocrine (NE) features [1]. This trans-differentiation induces complete androgen-independence and promotes metastatic spreading. NE-PCas are currently incurable and associated with a dismal prognosis (median survival shorter than 1 year). Therefore, there is a dire need for the identification of effective therapeutic targets for this aggressive malignancy. Calcium dynamics govern key aspects of cellular phenotypes, including tissue specification, motility and proliferation. Notably, calcium-dependent alterations are reversible and targetable by small molecule inhibitors. Increasing evidence suggests that the alteration of calcium dynamics affects the initiation and progression of some malignancies. For example, we have shown that T-type calcium channels drive the proliferation of castration-resistant PCa [2]. However, the calcium signalling toolkit is organised in a complex network of interacting molecules. This interactome has never been explored systematically in the context of a specific malignancy. In this project, we propose to study the role of calcium-dependent genes in NE-PCa pathogenesis, with the ultimate goal of identifying new therapeutic targets

The student will examine the role of a family of proteins that protect cells from a form of death known as 'apoptosis'. In particular, the student will examine how the 'Bcl-2' affects cellular calcium transport. The working hypothesis is that Bcl-2 prevents the transfer of calcium between cellular compartments to avoid triggering apoptosis.

Lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) affect the lives of millions of people in the UK. Whilst the number of patients diagnosed with lung disease increases each year, the treatments available have changed very little over the past 30 years, despite large investment from pharmaceutical companies for the development of new treatments. One of the main reasons that many new medicines have not reached the market is the limited understanding of how the immune system in the lungs responds to the inhalation of therapeutic drug powders. Additionally, current methods used to test the safety of new inhaled medicines, rely on animal models which may not accurately predict safety in humans. Regulatory bodies are therefore unable to approve new medicines that appear to sensitise the immune system in animal models, despite not knowing fully if these observations are adverse in human patients. This project aims to better characterise inflammatory responses in the lung to inhaled medicines. Commercially available cell based models of the lung will be used, and imaging, biological and analytical tools will be employed to determine the reactions to inhaled medicines. The ultimate goal will be to use non-animal methods to provide an in depth understanding of the immune responses in the lung to reduce the numbers of animal experiments required to achieve an accurate prediction of the safety of new inhaled medicines in humans.

This is a collaborative project with the MRC Human Nutrition Research Unit in Cambridge. They have a long-standing interest in understanding how peptidoglycans released by bacteria in the gut lead to dampening of immune responses. The current hypothesis suggests that the peptidoglycans are transported across the gut wall through specialized uptake cells because they are encased in a calcium-phosphate matrix. Following their transport across the gut wall, the peptidoglycan/calcium-phosphate nanoparticles are endocytosed by white blood cells that consequently express a death receptor ligand. This study will investigate the role of the mineral component of the peptidoglycan/calcium-phosphate nanoparticles, and examine whether Crohn's patients have a different response to normal, in that they cannot process the calcium deposit and it leads to abnormal cell function.

This is a collaborative project with the MRC Human Nutrition Research Unit in Cambridge. They have a long-standing interest in understanding how peptidoglycans released by bacteria in the gut lead to dampening of immune responses. The current hypothesis suggests that the peptidoglycans are transported across the gut wall through specialized uptake cells because they are encased in a calcium-phosphate matrix. Following their transport across the gut wall, the peptidoglycan/calcium-phosphate nanoparticles are endocytosed by white blood cells that consequently express a death receptor ligand. This study will investigate the role of the mineral component of the peptidoglycan/calcium-phosphate nanoparticles, and examine whether Crohn's patients have a different response to normal, in that they cannot process the calcium deposit and it leads to abnormal cell function. (This record is supplementary to AMS record 171480 which covers the original studentship. Due to the withdrawal of a second student, we are recruiting a third - Fraser McDonald has agreed to fund the 1 year stipend shortfall at £14,553).

Creation and development of a fibrin-based pro-angiogenic tissue matrix type scaffold. The goal is optimise the strutcure of the material to support mesenchymal stem cell pro-angiogenic and immuno-modulatory function for dermal and connective tissue reconstruction of chronic ulcers. The project involves a collaboration between the OU, the Institute of Biomedical Engineering at UCL (UCL IBME) and Cells for Cells, a Chilean Cell therapy company (C4C) spun out from University of Los Andes (UANDES) managed by a grant adminstration compay, Regenero.

Lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) affect the lives of millions of people in the UK. Whilst the number of patients diagnosed with lung disease increases each year, the treatments available have changed very little over the past 30 years, despite large investment from pharmaceutical companies for the development of new treatments. One of the main reasons that many new medicines have not reached the market is the limited understanding of how the immune system in the lungs responds to the inhalation of therapeutic drug powders. Additionally, current methods used to test the safety of new inhaled medicines, rely on animal models which may not accurately predict safety in humans. Regulatory bodies are therefore unable to approve new medicines that appear to sensitise the immune system in animal models, despite not knowing fully if these observations are adverse in human patients. This project aims to better characterise inflammatory responses in the lung to inhaled medicines. Commercially available cell based models of the lung will be used, and imaging, biological and analytical tools will be employed to determine the reactions to inhaled medicines. The ultimate goal will be to use non-animal methods to provide an in depth understanding of the immune responses in the lung to reduce the numbers of animal experiments required to achieve an accurate prediction of the safety of new inhaled medicines in humans.

‘The Biochemical Society’s Eric Reid Fund for methodological development. The grant is to optimise development of a functional coculture of adipocytes and cardiomyocytes.’