or
Continue with FacebookLooking to list your PhD opportunities? Log in here.
This project is no longer listed on FindAPhD.com and may not be available.
Click here to search FindAPhD.com for PhD studentship opportunities
Dr J Madine
Prof D J Rigden
Applications accepted all year round
About the Project
Amyloid deposits in the heart and blood vessels are associated with various cardiovascular diseases and are prevalent in the ageing population. This project will examine two proteins as model systems for amyloidoses which infiltrate the cardiovascular system; SMA and medin.
Part of this project relates to the tendency of amyloid deposits to associate with cell membranes. The association has two consequences, an acceleration of amyloid formation and a destabilisation of the membrane, each with potential implications for toxicity. However, it remains unclear if membrane association in general or the presence of specific membrane components drives this deposition. This project aims to enhance understanding of the assembly of cardiovascular amyloid and the role that membrane interactions play in influencing amyloid formation and deposition within the heart and aorta. A range of techniques will be used including binding studies (e.g. isothermal titration calorimetry, surface plasmon resonance), microscopy, multinuclear solid-state NMR and cell viability assays. Where possible, structure modelling of putative membrane-associated structures will be done and complementary sequence analysis of pathogenic and non-pathogenic relatives undertaken.
A second component of the project will run alongside on-going research elsewhere in the group studying the aggregation properties of cardiovascular amyloid proteins. To complement the biophysical studies, bioinformatics tools will be employed to model the structural conformations of the proteins upon aggregation into pathogenic amyloid fibrils. This modelling is an essential tool to understand the cytotoxic potential of the proteins at specific stages throughout the aggregation process and identify the potentially toxic species involved in cardiovascular diseases. Molecular level understanding of these interactions and their pathogenic implications will be used to design and test template drugs that target amyloid assembly for therapeutic intervention.
Training:
The project will provide comprehensive exposure to biophysical methods as well as to tools of sequence- and structure-based protein bioinformatics. The student will gain specific training in methods for approaching pathological mechanisms of age-related diseases, a research area of ever-growing importance to ageing populations.
Part of this project relates to the tendency of amyloid deposits to associate with cell membranes. The association has two consequences, an acceleration of amyloid formation and a destabilisation of the membrane, each with potential implications for toxicity. However, it remains unclear if membrane association in general or the presence of specific membrane components drives this deposition. This project aims to enhance understanding of the assembly of cardiovascular amyloid and the role that membrane interactions play in influencing amyloid formation and deposition within the heart and aorta. A range of techniques will be used including binding studies (e.g. isothermal titration calorimetry, surface plasmon resonance), microscopy, multinuclear solid-state NMR and cell viability assays. Where possible, structure modelling of putative membrane-associated structures will be done and complementary sequence analysis of pathogenic and non-pathogenic relatives undertaken.
A second component of the project will run alongside on-going research elsewhere in the group studying the aggregation properties of cardiovascular amyloid proteins. To complement the biophysical studies, bioinformatics tools will be employed to model the structural conformations of the proteins upon aggregation into pathogenic amyloid fibrils. This modelling is an essential tool to understand the cytotoxic potential of the proteins at specific stages throughout the aggregation process and identify the potentially toxic species involved in cardiovascular diseases. Molecular level understanding of these interactions and their pathogenic implications will be used to design and test template drugs that target amyloid assembly for therapeutic intervention.
Training:
The project will provide comprehensive exposure to biophysical methods as well as to tools of sequence- and structure-based protein bioinformatics. The student will gain specific training in methods for approaching pathological mechanisms of age-related diseases, a research area of ever-growing importance to ageing populations.
References
1. Madine, J., E. Hughes, A.J. Doig, and D.A. Middleton, The effects of α-synuclein on phospholipid vesicle integrity: a study using 31P NMR and electron microscopy. Molecular Membrane Biology, 2008. 25(6-7): p. 518-527.
2. Meng, X., A.L. Fink, and V.N. Uversky, The effect of membranes on the in vitro fibrillation of an amyloidogenic light-chain variable-domain SMA. Journal of Molecular Biology, 2008. 381(4): p. 989-999.
3. Olofsson, A., T. Borowik, G. Grobner, E.A. Sauer-Eriksson, Negatively charged phospholipid membranes induce amyloid formation of medin via an α-helical intermediate. Journal of Molecular Biology, 2007. 374(1): p. 186-194.
2. Meng, X., A.L. Fink, and V.N. Uversky, The effect of membranes on the in vitro fibrillation of an amyloidogenic light-chain variable-domain SMA. Journal of Molecular Biology, 2008. 381(4): p. 989-999.
3. Olofsson, A., T. Borowik, G. Grobner, E.A. Sauer-Eriksson, Negatively charged phospholipid membranes induce amyloid formation of medin via an α-helical intermediate. Journal of Molecular Biology, 2007. 374(1): p. 186-194.
Project supervisors
Career overview
Dr Jill Madine obtained a BSc in Biochemistry from the University of Manchester Institute for Science and Technology (UMIST). She then completed a PhD at the University of Manchester, where she studied the mechanism of alpha-synuclein aggregation in Lewy body disease. Following her doctoral studies, Dr Madine was awarded an Alzheimer''s Research UK Fellowship to investigate the structure-based design of modified peptides for the inhibition of α-synuclein aggregation, subsequently moving to the University of Liverpool in 2006. Her work at Liverpool has predominantly focused on a project investigating the structural modulation of a-beta fibrils and intermediates by glycosaminoglycans, along with several projects exploring the structure of peptide-nanotubes as potential biomaterials. Dr Madine was awarded a British Heart Foundation Intermediate Basic Science Research Fellowship to investigate amyloid deposition in the cardiovascular system. During this fellowship, she co-established the multidisciplinary Liverpool Aortic Biomechanics and Biochemistry Research group, which aims to understand the underlying mechanisms in aortic conditions in collaboration with Liverpool Heart and Chest Hospital. In addition to this area of research, her group is currently exploring the role and inhibition of amyloid protein aggregation in systemic, neurodegenerative, and cardiovascular diseases. Positions are available for PhD study in her research group focusing on cardiovascular and neurodegenerative conditions.
Research interests
Dr Madine''s research focuses on the mechanisms of protein aggregation, particularly in relation to neurodegenerative diseases such as Lewy body disease and Alzheimer''s disease. She has investigated the structure-based design of modified peptides to inhibit α-synuclein aggregation and has worked on the structural modulation of amyloid-beta fibrils and intermediates by glycosaminoglycans. Additionally, Dr Madine has explored amyloid deposition in the cardiovascular system and co-established the Liverpool Aortic Biomechanics and Biochemistry Research group, which aims to understand the underlying mechanisms in aortic conditions. Her current research group is also involved in studying the role and inhibition of amyloid protein aggregation in systemic, neurodegenerative, and cardiovascular diseases.
Biochemistry
Cell Biology
Systems Biology
Alpha-Synuclein Aggregation
Lewy Body Disease
Structure-Based Design
Modified Peptides
Amyloid Deposition
Cardiovascular System
Aortic Biomechanics
Biochemistry Research
Neurodegenerative Diseases
Peptide-Nanotubes
Biomaterials
Glycosaminoglycans
Amyloid Protein Aggregation
Systemic Diseases
Research Fellowships
Multidisciplinary Research
PhD Opportunities.
Career overview
Professor Dan Rigden is a Professor of Protein Bioinformatics at the University of Liverpool, affiliated with the Institute of Systems, Molecular and Integrative Biology. His research interests encompass the relationships between protein sequences, structures, and functions, as well as their evolutionary dynamics. Professor Rigden employs a variety of bioinformatics tools, particularly modelling software such as AlphaFold 2, to investigate diverse proteins. His work fosters collaborations within the Institute and beyond. He is involved in the development of structural bioinformatics applications aimed at enhancing experimental structural biology. A significant focus of his research includes solving crystal structures through Molecular Replacement, utilising unconventional protein models via the AMPLE program and detecting crystallisation contaminants with the SIMBAD tool, both of which are part of the CCP4 suite. Additionally, he is engaged in developing methods for interpreting and fitting cryo-electron microscopy (cryo-EM) maps and validating protein structures. Professor Rigden is also open to supervising PhD students in the areas of protein structure, function, evolution, and crystallographic or cryo-EM methodologies.
Research interests
Professor Rigden''s research focuses on the relationships between protein sequences, structures, and functions, as well as their evolution over time. He applies a variety of bioinformatics tools, particularly modelling software like AlphaFold 2, to diverse proteins of interest. His work includes the development of software for experimental structural biology, with a primary interest in solving crystal structures through Molecular Replacement. This involves the use of unconventional protein models, exemplified by the program AMPLE, and the detection of crystallisation contaminants using SIMBAD, both of which are part of the CCP4 suite. Additionally, he is interested in methods development for cryo-electron microscopy (cryo-EM) map interpretation and fitting, as well as protein structure validation. Professor Rigden also offers positions for PhD study in protein structure-function-evolution and crystallographic or cryo-EM methods.
Protein Bioinformatics
Protein Sequences
Protein Structures
Protein Functions
Evolution
Bioinformatics Tools
Modelling Software
AlphaFold 2
Structural Bioinformatics
Experimental Structural Biology
Molecular Replacement
Unconventional Protein Models
AMPLE
Crystallisation Contaminant Detection
SIMBAD
CCP4 Suite
Cryo-EM Map Interpretation
Protein Structure Validation
Methods Development
PhD Study
Protein Structure-Function-Evolution
Crystallographic Methods
Cryo-EM Methods
Find a scholarship to fund your dream Masters
Sign in to view and filter all scholarship opportunities
or
Continue with Facebook