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Dr E W Hewitt
Prof Sheena Radford
Dr Paolo Actis
Applications accepted all year round
Self-Funded PhD Students Only
About the Project
Interested in amyloid disorders such as Parkinson’s and Huntington’s. Want to work with cutting edge technology in a multidisciplinary team. Then this could be the project for you!
The aim of this project is to use a nanoinjection platform for the quantitative and targeted delivery of amyloid fibrils and oligomers into cells for functional analysis.
Diseases such as Parkinson’s disease and Huntington’s disease are associated with the aggregation of proteins into amyloid fibrils, which form the intracellular inclusions that are a hallmark of these disorders. Whilst, significant progress has been made in the determining the structure of amyloid fibrils and their oligomeric intermediates, to understand how amyloid formation results in cell death and tissue destruction these findings need to be integrated with studies of their biological properties. This is a particularly challenging for proteins, such as alpha-synuclein (Parkinson’s) and huntingtin (Huntington’s), which assemble into amyloid fibrils inside cells.
The nanoinjection platform uses quartz needles with ≤50nm diameter pores, known as nanopipettes, to inject macromolecules into cells. Due to the small size of the pore individual macromolecules can be detected when they are delivered into cells, thus cellular delivery can be quantified. We will use the nanoinjection platform to deliver amyloid fibrils and their oligomeric assembly intermediates into cells. A defined number of structurally characterised amyloid fibrils and oligomers will be delivered by nanoinjection into the cytoplasm and nuclei of cells. The effect of these protein complexes on cells will be determined using microscopy-based assays for cellular stress and viability. Thus for the first time will be able to determine not only which amyloid fibrils and oligomers are toxic inside cells, but also how many of each it takes to make a cell sick and die.
This project is highly collaborative and multidisciplinary and the supervisory team’s labs combine expertise in cell biology (Eric Hewitt), amyloid structure and assembly (Sheena Radford) and nanotechnology (Paolo Actis)
Please contact Dr Eric Hewitt ([Email Address Removed]) if you have any questions about the project
The aim of this project is to use a nanoinjection platform for the quantitative and targeted delivery of amyloid fibrils and oligomers into cells for functional analysis.
Diseases such as Parkinson’s disease and Huntington’s disease are associated with the aggregation of proteins into amyloid fibrils, which form the intracellular inclusions that are a hallmark of these disorders. Whilst, significant progress has been made in the determining the structure of amyloid fibrils and their oligomeric intermediates, to understand how amyloid formation results in cell death and tissue destruction these findings need to be integrated with studies of their biological properties. This is a particularly challenging for proteins, such as alpha-synuclein (Parkinson’s) and huntingtin (Huntington’s), which assemble into amyloid fibrils inside cells.
The nanoinjection platform uses quartz needles with ≤50nm diameter pores, known as nanopipettes, to inject macromolecules into cells. Due to the small size of the pore individual macromolecules can be detected when they are delivered into cells, thus cellular delivery can be quantified. We will use the nanoinjection platform to deliver amyloid fibrils and their oligomeric assembly intermediates into cells. A defined number of structurally characterised amyloid fibrils and oligomers will be delivered by nanoinjection into the cytoplasm and nuclei of cells. The effect of these protein complexes on cells will be determined using microscopy-based assays for cellular stress and viability. Thus for the first time will be able to determine not only which amyloid fibrils and oligomers are toxic inside cells, but also how many of each it takes to make a cell sick and die.
This project is highly collaborative and multidisciplinary and the supervisory team’s labs combine expertise in cell biology (Eric Hewitt), amyloid structure and assembly (Sheena Radford) and nanotechnology (Paolo Actis)
Please contact Dr Eric Hewitt ([Email Address Removed]) if you have any questions about the project
Funding Notes
Self-funded students: International or domestic self-funded or scholarship/fellowship PhD students are always welcome to apply. International students must have a good command of both written and spoken English. In addition to University fees, laboratory fees will be required if you are self-funded. Applications can be made throughout the year.
References
Some of our recent papers:
Actis P et al (2014). Electrochemical nanoprobes for single-cell analysis. ACS Nano. 8: 875-84
Jakhria et al (2014). β2-microglobulin amyloid fibrils are nanoparticles that disrupt lysosomal membrane protein trafficking and inhibit protein degradation by lysosomes. J Biol Chem 289: 35781-94
Tipping et al (2015). pH-induced molecular shedding drives the formation of amyloid fibril-derived oligomers. Proc Natl Acad Sci U S A. 112: 5691-6
Iadanza et al (2018). The structure of a β2-microglobulin fibril suggests a molecular basis for its amyloid polymorphism.Nat Commun. 9: 4517.
Karamanos et al (2019). Structural mapping of oligomeric intermediates in an amyloid assembly pathway. Elife. 8: e46574.
Nadappuram et al (2019) Nanoscale Tweezers for Single-Cell Biopsies Nature Nanotechnology 14: 80-88
Actis P et al (2014). Electrochemical nanoprobes for single-cell analysis. ACS Nano. 8: 875-84
Jakhria et al (2014). β2-microglobulin amyloid fibrils are nanoparticles that disrupt lysosomal membrane protein trafficking and inhibit protein degradation by lysosomes. J Biol Chem 289: 35781-94
Tipping et al (2015). pH-induced molecular shedding drives the formation of amyloid fibril-derived oligomers. Proc Natl Acad Sci U S A. 112: 5691-6
Iadanza et al (2018). The structure of a β2-microglobulin fibril suggests a molecular basis for its amyloid polymorphism.Nat Commun. 9: 4517.
Karamanos et al (2019). Structural mapping of oligomeric intermediates in an amyloid assembly pathway. Elife. 8: e46574.
Nadappuram et al (2019) Nanoscale Tweezers for Single-Cell Biopsies Nature Nanotechnology 14: 80-88
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Career overview
Dr. Eric Hewitt obtained a PhD from the University of Manchester in 1994. Following this, he undertook postdoctoral work at the University of Dundee, University College London, and the University of Cambridge. He was appointed as a Lecturer at the University of Leeds in 2002 and progressed to Senior Lecturer/Associate Professor in 2011. Dr. Hewitt is currently an Associate Professor in the School of Molecular and Cellular Biology at the University of Leeds, where he also leads a research group and serves as the Head of the Faculty of Biological Sciences Graduate School.
Research interests
Dr Hewitt''s research focuses on the endocytic pathway and lysosomes in health and disease, investigating the roles of potassium ion channels in the trafficking of molecules and the function of lysosomes. He is also engaged in studying the cell biology of amyloid disease, particularly the formation of amyloid fibrils associated with disorders such as Alzheimer’s and Parkinson’s diseases. His work aims to understand the mechanisms of amyloid toxicity and involves a multidisciplinary approach that integrates structural biology techniques with cell biological analyses. Current projects include exploring a novel single molecule platform, nanoinjection, for delivering amyloid aggregates into cells for functional analysis. Additionally, Dr Hewitt has a longstanding interest in molecular immunology, specifically in antigen presentation by MHC molecules and how viruses evade immune detection. His current research includes exploring the role of anti-MHC antibodies in graft rejection and the misfolding of beta2-microglobulin in dialysis-related amyloidosis.
Cell Biology
Molecular Immunology
Endocytic Pathway
Lysosomes
Health and Disease
Potassium Ion Channels
Amyloid Disease
Alzheimer’s
Parkinson’s
Type 2 Diabetes
Dialysis-Related Amyloidosis
Antigen Presentation
MHC Molecules
Immune System
Graft Rejection
Beta2-Microglobulin
Misfolding
Amyloid Toxicity
Structural Biology
Cell Biological Analyses
Nanoinjection
Protein Aggregates
Functional Analysis.
Career overview
Professor Sheena Radford joined the University of Leeds in 1995 as a Lecturer in the School of Biochemistry and Molecular Biology, progressing to Reader in 1998 and Professor in 2000. In 2009, she became the Deputy Director of the Astbury Centre for Structural Molecular Biology, and served as its Director from 2012 to 2021. She was appointed Astbury Professor of Biophysics in 2014 and became a Royal Society Research Professor in 2021. Professor Radford graduated with a BSc in Biochemistry from the University of Birmingham and completed her PhD in Biochemistry at the University of Cambridge under the supervision of Professor R.N. Perham, FRS. She has held various postdoctoral positions and a Royal Society University Research Fellowship at the Oxford Centre for Molecular Sciences. Throughout her career, Professor Radford has supervised around 25 PhD students and postdoctoral researchers in her laboratory, with over 160 individuals successfully progressing from her lab into various careers in academic research, industry, and technical editing. She has published more than 360 peer-reviewed papers and book chapters and has delivered over 475 invited lectures at national and international conferences across numerous countries. In the last five years, she has served on five major research funding panels and 20 Scientific Advisory Boards for prestigious institutions and companies. Additionally, she has been involved with editorial boards for several journals and currently serves as an Associate Editor for the Journal of Molecular Biology. She is also a Trustee and Council member of the Dementia Research Institute, UK, and the Regional Champion for the Academy of Medical Sciences. Professor Radford has received multiple awards, including the Biochemical Society Colworth Medal in 1996, the Royal Society of Chemistry AstraZeneca Prize in 2005, the Hites Award from the American Society for Mass Spectrometry in 2009, the Protein Society Carl Branden Award in 2013, and the Rita and John Cornforth Award of the Royal Society of Chemistry in 2015. She was elected a member of EMBO in 2007, a member of Academia Europaea in 2020, and has been recognised as a Fellow of the Academy of Medical Sciences (2010), the Royal Society (2014), and the Royal Society of Biology (2021). She was made an honorary member of the British Biophysical Society in 2014 and a Fellow of the Biophysical Society in 2018. In 2022, she received an honorary doctorate from the University of Liège, and in 2024, she became an International Member of the National Academy of Sciences (USA).
Research interests
Professor Radford''s research focuses on fundamental structural molecular biology, specifically the measurement of the conformational dynamics of proteins and the elucidation of the role that these motions play in protein folding and misfolding of both water-soluble and membrane proteins. Their research employs a wide range of biophysical methods, combining techniques from protein chemistry, molecular biology, chemical biology, and structural biology. Over the last 35 years, they have concentrated on delineating the mechanisms by which proteins fold or misfold, how dynamic excursions enable proteins to self-associate into amyloid fibrils—which are complex macromolecular assemblies associated with some of the deadliest human diseases—and how proteins fold into the bacterial outer membranes of Gram-negative organisms. Current major projects include: Mechanism(s) of protein misfolding and assembly into amyloid, Outer Membrane Protein (OMP) folding – The role of chaperones & BAM, Stabilising proteins of therapeutic interest against aggregation, Method development (MS, NMR, single molecule, biophysical methods).
Protein Folding
Protein Misfolding
Protein Aggregation
Amyloid
Membrane Protein Folding
Biopharmaceuticals
Structural Molecular Biology
Biophysical Methods
Protein Chemistry
Chemical Biology
Cell Biology
Conformational Dynamics
Mechanisms of Protein Folding
Therapeutic Proteins
Dynamic Excursions
Self-Association
Gram-Negative Bacteria
Chaperones
Method Development
Mass Spectrometry
NMR
Single Molecule Techniques.
Career overview
Dr Paolo Actis is an Associate Professor of Bio-nanotechnology at the University of Leeds. He graduated in 2008 with a PhD from the Grenoble Institute of Technology in France. Following his graduation, Dr Actis spent four years in California, where he worked at NASA Ames and the University of California, Santa Cruz. He then moved to the UK to work at Imperial College London before spending two years at Bio Nano Consulting as a Consultant and Project Manager. Dr Actis''s research focuses on the development of nanoprobes for single-cell analysis and manipulation with single molecule resolution, collaborating with biologists and physicians to differentiate between healthy and diseased cells.
Research interests
Dr Actis''s research focuses on the development of nanoprobes for single-cell analysis and manipulation with single molecule resolution. He collaborates with biologists and physicians to explore the differences between healthy and diseased cells. His research plan aims to create a new platform for single-cell analysis to study the dynamic functions of individual cells within heterogeneous populations. His specific research interests include: Single-cell Nanosurgery, developing an electrical nanobiopsy platform for extracting genetic material and organelles from single cells; Single molecule Biosensing, working on functionalised DNA origami constructs for capturing disease biomarkers; Single-molecule Nanoinjection, developing a platform for injecting biomolecules into living cells to understand neurodegeneration mechanisms in Parkinson''s disease; and engaging in interdisciplinary collaborations with artists and chefs.
Bio-nanotechnology
Nanopores
Biosensor
Single-Cell Analysis
Single Molecule Analysis
Electrochemistry
Nanoprobes
Nanosurgery
Genetic Material Extraction
Disease Biomarkers
Nanopore Sensors
Single-Molecule Nanoinjection
Neurodegeneration
Parkinson’s Disease
Brain Cancer
GBM
Functionalized DNA Origami
Heterogeneous Populations
Dynamic Function
Student Education
Medical Electronics
e-Health.
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