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Aiming to elucidate the pathophysiological basis of human neurological disorders from genetic molecular networks to complex neural systems.

Translational molecular neuroscience group 6

 

About the Research

Our lab is interested in developing novel tools, resources and approaches to enable discovery of new therapies for patients with neurological disorders. We use human induced pluripotent stem cell (IPSC) models to generate brain constituent cell types from neurons to microglia to the cerebral vasculature. We then using omics technique such as single cell transcriptomics to identify disease signatures and relate these to cellular disease phenotypes.  In order to identify cellular phenotypes we use microscopy, calcium imaging, multi-electrode arrays and patch clamp electrophysiology as well as the usual molecular biology techniques. We have successfully used this approach to find a novel activator of the two potassium channel TRESK, which is now being developed as a pain therapeutic


There are two main areas that we would welcome a new student to undertake research:


The first is on understanding the molecular mechanisms of autism and how gene-environment interaction may affect human cellular phenotypes and drug responses. We have been investigating how loss of function of the gene, TSC2 can alter neural progenitor cell cycle and subsequent cell fate choices leading to greater production of glia. The glial-neuronal imbalance is significantly altered by nutrients in the cell culture media highlighting the important of gene-environment interactions. We believe that the glial-neuronal imbalance then alters neuronal circuit function causing autism and promoting epileptogenesis.  


The second area is on the role of brain endothelial cells in the development of dementia. Neurovascular interactions are fundamental to brain function and compromise of the neurovascular unit occurs early in dementia. We have developed a new protocol to generate brain endothelial cells from iPSC and demonstrated it can form an effective blood-brain-barrier. We would now like to investigate how brain endothelial cells generated from Alzheimer’s patients can affect endothelial cell function and how neurovascular interactions may be changed.

 

Training Opportunities

The student will be trained in stem cell culture and differentiation. Depending on the project the student would also be trained in omics profiling such as single cell RNA sequencing and epigenetic studies; electrophysiology approaches such multi-electrode arrays and patch-clamp electrophysiology; and functional assays such as calcium imaging. There will also be training on analysis of the data generated by each of these methods

 

Students will be enrolled on the MRC WIMM 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.

All MRC WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the MRC WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework. The RDM also holds 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.

 

Publications

Volpato V, Smith J, Sandor C, Ried JS, Baud A, Handel A, Newey SE, Wessely F, Attar M, Whiteley E, Chintawar S, Verheyen A, Barta T, Lako M, Armstrong L, Muschet C, Artati A, Cusulin C, Christensen K, Patsch C, Sharma E, Nicod J, Brownjohn P, Stubbs V, Heywood WE, Gissen P, De Filippis R, Janssen K, Reinhardt P, Adamski J, Royaux I, Peeters PJ, Terstappen GC, Graf M, Livesey FJ, Akerman CJ, Mills K, Bowden R, Nicholson G, Webber C, Cader MZ, Lakics V. Reproducibility of Molecular Phenotypes after Long-Term Differentiation to Human iPSC-Derived Neurons: A Multi-Site Omics Study. Stem Cell Reports. 2018 Sep 6.

Parkes I, Chintawar S, Cader MZ. Neurovascular dysfunction in dementia – human cellular models and molecular mechanisms. Clinical science 2018; 132(3):399-418.

Haenseler W,.., Cader MZ, et al. A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response. Stem Cell Reports. 2017 Jun 6;8(6):1727-1742.

Handel AE,.., Cader MZ. Assessing similarity to primary tissue and cortical layer identity in induced pluripotent stem cell-derived cortical neurons through single-cell transcriptomics. Hum Mol Genet. 2016 Mar 1;25(5):989-1000.


Supervisors