Studies of amyloid beta and alpha-synuclein oligomerisation by microfluidic techniques

Alzheimer's (AD) and Parkinson's (PD) diseases are increasingly prevalent and currently incurable neurodegenerative disorders linked to the accumulation of proteinaceous pathogenic inclusions in the nerve system. Oligomerisation of misfolded amyloid beta and alpha-synuclein proteins is a key step in AD and PD-associated neurotoxicity. Therefore a detailed understanding of this phenomenon is crucial to find effective disease management and therapeutic strategies. However, despite the intensive effort put to understand aberrant protein oligomerisation and the downstream events, mechanistic details of oligomer-induced cellular toxicity are still missing. The project aims at characterising AD- and PD- relevant oligomers at a single-molecule level, to the level of depth and complexity inaccessible by conventional biophysical techniques before. The project outcomes will fill in the gap of knowledge in disease-linked oligomer formation, evolution, diversity, interactions with cellular binding partners and, importantly, implications in neurotoxicity. A set of microfluidic techniques combined with an advanced single-molecule optical detection strategy will be employed to address the challenges faced in biophysical oligomer characterisation studies, namely transient nature, heterogeneity and low abundance of the species. The work will be carried out in close collaboration with Fluidic Analytics Ltd, a company developing and commercialising novel microfluidic tools for protein biophysics. The project is highly interdisciplinary and lies in the areas of biophysics and soft matter physics, as well as chemical biology and biological chemistry.

The primary outputs from the CDT will be cohorts of highly qualified, interdisciplinary postgraduates who are experts in a wide range of sensing activities. They will benefit from a world leading training experience that recognises sensor research as an academic discipline in its own right. The students will be taught in all aspects of Sensor Technologies, ranging from the physical and chemical principles of sensing, to sensor design, data capture and processing, all the way to applications and opportunities for commercialisation, with a strong focus in entrepreneurship, technology translation and responsible leadership. Students will learn in extensive team and cohort engaging activities, and have access to cutting-edge expertise and infrastructure. 90 academics from 15 different departments participate in the programme and more than 40 industrial partners are actively involved in delivering research and business leadership training, offering perspectives for impact and translation and opportunities for internships and secondments. End users associated with the CDT will benefit from the availability of outstanding, highly qualified and motivated PhD students, access to shared infrastructure, and a huge range of academic and industrial contacts.

Immediate beneficiaries of our CDT will be our core industrial consortium partners (MedImmune, Alphasense, Fluidic Analytics, ioLight, NokiaBell, Cambridge Display Technologies, Teraview, Zimmer and Peacock, Panaxium, Silicon Microgravity, etc., see various LoS) who incorporate our cross-leverage funding model into their corporate research strategies. Small companies and start-ups particularly benefit from the flexibility of the partnerships we can offer. We will engage through weekly industry seminars and monthly Sensor Cafés, where SME employees can interact directly with the CDT students and PIs, provide training in topical areas, and, in turn, gain themselves access to CDT infrastructure and training. Ideas can be rapidly tested through industrially focused miniprojects and promising leads developed into funded PhD programmes, for which leveraged funding is available through the CDT.

Government departments and large research initiatives are formally connected to the CDT, including the Department for the Environment, Food and Rural Affairs (DEFRA); the Cambridge Centre for Smart Infrastructure and Construction (CSIC); the Centre for Global Equality (CGE); the National Physics Laboratory (NPL); the British Antarctic Survey (BAS), who all push our CDT to generate impacts that are in the public interest and relevant for a healthy and sustainable future society. With their input, we will tackle projects on assisted living technologies for the ageing population, diagnostics of environmental toxins in the developing world, and sensor technologies that help replace the use of animals in research. Developing countries will benefit through our emphasis on open technologies / open innovation and our exploration of responsible, ethical, and transparent business models. In the UK, our CDT will engage directly with the public sector and national policy makers and regulators (DEFRA, and the National Health Service - NHS) and, with their input, students are trained on impact and technology translation, ethics, and regulatory frameworks.