Lewis Group: Imaging mitochondrial trafficking and dynamics in the failing heart

This is an ambitious and highly collaborative project in which you will leverage the expertise and capabilities of three complementary supervisors, their groups and resources to generate new insights into abnormal mitochondrial dynamics in the failing heart.

About the Research 

Heart failure is a devastating disease, and cardiac mitochondrial dysfunction is both a hallmark of heart failure and a compelling target for novel therapies. Previous work in our groups and others has identified a critical role for abnormal mitochondrial housekeeping and trafficking as hearts fail, resulting in accumulation of free extracellular mitochondria. The precise cellular mechanisms which underpin these processes are uncertain, but could now be studied using a range of sophisticated cellular and tissue-based approaches. This proposed DPhil project has 3 main workstreams. The first workstream will involve the creation of the primary model system for the project – beating iPS cardiomyocytes carrying genetic mutations known to cause heart failure (led by supervisor Toepfer) -  coupled with genetic engineering and state of the live-cell and mitochondrial microscopy. In the second workstream, you will conduct sophisticated particle analysis of extracellular free mitochondrial fragments, using techniques and methods already optimised to study vesicle-size particles, including flow cytometry (led by supervisor Akbar). In the third workstream, you will utilise spatial transcriptomics of precious human heart failure samples, coupled with complementary electron microscopy, to document the translational relevance of your findings (led by supervisor Lewis). All project workstreams will incorporate sophisticated computational approaches incorporating bioinformatics. At the conclusion of the project, you will have developed expertise in a range of state-of-the-art biomedical techniques and methods, and will have generated new insights into mechanisms underlying heart failure.

Training Opportunities

• iPS cardiomyocyte generation and cell culture
• Genetic engineering using CRISPR/Cas9
• Sanger Sequencing
• Live cell imaging and microscopy
• Particle tracking and analysis including flow cytometry
• Spatial genomics and transcriptomics
• Electron microscopy
• Extracellular vesicles isolation and characterisation
• Nanoparticle Tracking Analysis (NTA)
• CRISPR/Cas-9 genome engineering and PCR
• Lentivrial production
• RT-qPCR
• Western blotting
• Transmission electronic microscopy (TEM) and cryo-TEM
• Fluorescent microscopy and confocal microscopy.
• RNA-Arrays and sequencing, proteomics, lipidomics, metabolomics.
• Bioinformatics

Students will be enrolled on the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence, and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Additional supervisors

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