Recent grants and funding - 2015

Lotteries Health Research Translational Research Project

Joanna Mackichan

Title: Nutritional adaptation as a virulence factor: investigation into the differences between disease- and carriage-associated meningococci

Meningococcal disease is a much-feared illness with rapid onset, often striking previously healthy children. However, the causative bacterium is frequently carried harmlessly in the throat, where most isolates are benign and not associated with disease. Invasive forms of meningococcal disease, including meningococcal septicaemia or meningitis, are associated with highly virulent (disease-associated) strains. The bacterial factors that underpin differences in virulence remain relatively poorly understood. We have shown that disease-associated meningococcal isolates are able to inhibit migration of host cells in an in vitro assay; our preliminary evidence also suggests that disease- and carriage-associated isolates differ in how essential nutrients are acquired, with these differences underpinning variations in their interactions with host cells. The goal of this research is to test our hypothesis that bacterial nutrient piracy, in particular the acquisition of the essential elements iron and zinc, disrupts host cell function and plays a role in meningococcal virulence.

Worldwide Cancer Research Grant

Gary Evans, Joanne Harvey, Peter Northcote & Paul Teesdale-Spittle

Title: Developing pateamine for eIF4A-directed therapies

Pateamine is a natural product isolated from marine sponges off the coast of New Zealand. It is potent at killing cancer cells, and has recently been shown to be able to stop the production of deleterious proteins in cells, even at very low doses. It achieves this activity through disrupting the function of a key gatekeeper of cellular protein production, the eukaryotic initiation factor 4A (eIF4A). This activity has been shown to be powerful in the treatment of the uncontrolled muscle loss that goes along with cancer (cachexia) and for overcoming drug resistance when it arises in lymphomas, leukaemia and melanomas.

Whilst pateamine is the most potent molecule known to disrupt eIF4A, its supply from the natural source is limited. To unlock the therapeutic potential of agents that target eIF4A, we will provide more of the natural product through both isolation and synthesis. However, whilst pateamine is very potent, there is no reason to expect that the structure of a compound isolated from a marine sponge should be optimal for treating human disease. We will also develop new structural variants to test for improved characteristics.

Falk Medical Research Foundation Catalyst Research Grant

David Ackerley (Jeff Mumm & Maria Canto-Soler)

Title: Human iPS Cell-Derived Mini-Retina Disease Modeling System - Optimization for Drug Discovery

Retinal degenerative diseases cause the dysfunction and death of retinal photoreceptor cells, leading to vision loss, and eventually, total blindness. Unfortunately, these diseases remain incurable. In this context, human stem cell-based approaches present unique clinical and scientific opportunities. In particular, human induced pluripotent stem cells (hiPSC) provide an unprecedented scenario for understanding the mechanisms underlying human degenerative diseases and identifying therapeutic agents. We have recently established the first 3D in vitro model of the human retina derived from hiPSC that faithfully recapitulates normal retinal development in vivo. Significantly, in our system photoreceptor cells develop outer segments (an essential ultrastructural feature) and light responsiveness—a first for the field. Despite this remarkable advance, our mini-retina prototype does not overcome one final challenge: a well-organized retinal pigmented epithelium (RPE) cell layer. This is important, as the RPE contributes to the development of many retinal pathologies. This issue presents a critical barrier for the field, underscoring the urgency for methodologies to overcome this obstacle in order to propel hiPSC technology into the clinical arena for the study and treatment of retinal diseases. The goal of this project is two-fold: 1) To develop the first human iPSC-derived retinal model consisting of a fully mature neural retina and associated RPE, and 2) To establish an inducible degenerative disease modeling system suited for high-throughput screening (HTS) drug discovery using our hiPSC-derived mini-retinas.