This proposal aims to develop a digital, ultrasensitive technique that can detect and quantify protein-induced membrane permeabilisation and disruption at the highest level of sensitivity. Disruption of membrane integrity is a ubiquitous mechanism by which protein aggregates confer toxicity in various human diseases, including Alzheimer's and Parkinson's disease, Type II diabetes, Sickle cell disease, and even specific type of Cancer. Toxic aggregates disrupt and permeabilise lipid bilayer of the cellular membrane and allow the influx of extracellular calcium ions, which leads to disrupted calcium homeostasis and cell death. In this work, we will fabricate nanosized probe to mimic the natural bilayer of cellular membrane and determine how protein aggregate damage membrane integrity. By utilising single-molecule localisation based super-resolution imaging, we will develop a quantitative method which will enable direct observation of individual protein aggregates induced lipid membrane permeabilisation in a high-throughput manner by counting the number of entering ions. This novel ultra-sensitive methodology will provide new insights into the mechanism of membrane permeabilisation in protein-misfolding disease, allowing us to identify and characterise the most toxic protein aggregates in complex human samples and screen the potential drug which can prevent or reduce protein aggregates induced membrane damage which is related to Alzheimer's and Parkinson's disease.
The supervisors combine expertise in biophysics including single-molecule and super-resolution imaging, biochemistry, molecular neuroscience (Dr Suman De), cellular and molecular pathology of dementia and brain ageing (Professor Stephen B Wharton). Due to the multidisciplinary nature of this project candidates from a wide variety of disciplines will be considered such as (but not limited to); any field of biology, chemistry and experimental physics. Previous working experience with protein aggregation, lipid bilayers, or imaging is advantageous.
The student will have the opportunity to gain training in a range of biophysical and biochemical techniques (including state-of-the-art single-molecule and super-resolution imaging, customised microscope building, imaging data analysis, protein purification and aggregation, histochemistry, basic molecular biology and biochemistry techniques) as well as analytical, interpersonal and project management skills. PhD students in the Sheffield Institute for Translational Neuroscience (SITraN) will have access to state-of-the-art instrumentation for cutting-edge research, mentorship programme and seminars delivered by the leading scientists from around the worlds.
Informal enquiries should be made to Dr Suman De ([Email Address Removed])
Entry Requirements:
Candidates must have a first or upper second class honours degree and experience working in a research laboratory is desirable.
How to apply:
Please complete a University Postgraduate Research Application form available here: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying
Proposed start date - October 2021
Continue with Facebook
