The Centre for Molecular Medicine: PhD opportunities 2012

Goal

To identify the underlying molecular pathways disrupted in schizophrenia and related major mental illnesses by gene expression profiling and pharmacological responses of neural stem cells derived from a Scottish family carrying a t(1;11) which disrupts the DISC1 locus and causes schizophrenia or related major mental illness

Co-Supervisors

Project Summary

Schizophrenia, bipolar disorder and recurrent major depression are devastating conditions for which current treatments are only partially effective. Lack of access to human neural tissue is a major limitation to developing more effective and better-tolerated treatments. To address this, we will harness the exciting potential of stem cell technology in which the University of Edinburgh is one of the world’s leading centres: human fibroblasts are routinely obtained through biopsy, cultured to become stem cells, then reprogrammed to become neurons, enabling us to study living human neural tissue. Critically, we also have access to the unique Scottish t(1;11) family carrying a causative disruption of the DISC1 gene: members have provided skin biopsies from which stem cells and neurons have already been obtained in two cases. This PhD project will characterise these cells at the molecular, cellular and pharmacological level. Using tools and techniques established in our laboratory, the student will profile these patient-derived stem cells as they form neurons and compare these profiles to normal cells. We will use the profiles to tell us what neural processes are perturbed in schizophrenia, and test how these respond to treatment with antipsychotics.

Methods to be employed & training provided:

Baseline characterisation

This is currently being carried out, so the student will have material available, but will benefit from exposure to the methods required for converting dermal skin biopsies to stem cells [1], then reprogrammed to become neurons and characterised using neuronal cell lineage specific markers and by electrophysiology.

Gene expression profiling and pathway analysis

Illumina whole genome expression profiling will be conducted on RNA samples from neuronal precursor stem cells and differentiated neurons in both translocation carriers and non-carriers [3]. Bioinformatics analysis by Gene Ontology and Pathway Analysis will be conducted to identify critical genes and processes that differentiate between affected and unaffected status [6].

Protein expression

In parallel, the expression of synaptic and signalling proteins, known to interact with DISC1 (including PDE4, GSK3beta, NDE1, NDEL1 and TNIK) or shown by the RNA analysis to be differentially expressed, will be measured by western blot analysis and immunohistochemistry [2, 4, 9, 11].

Pharmacology

The effect on neuralization and gene expression profiles of antipsychotics and antidepressants that are effective in translocation carriers and/or DISC1 mice will be tested [3, 4, 9].

Generic Research Training

The PhD student will be co-supervised by Profs. Porteous (1st) and McIntosh (2nd) who together offer a wide range of expertise in both basic and clinical science, and will meet regularly (at least weekly) with the candidate. The student will be trained in all of the techniques described in the proposal. They will attend regular Group and Section Meetings, at the IGMM and MRC Centre for Regenerative Medicine, and present their own work annually. Each student is assigned a Panel comprising the candidate, their supervisor(s), an independent Chair and an outside expert assessor, who meet formally to review progress, provide oversight and advice. The College Post-graduates Studies office provides extensive support, plus a programme of Transferable Skills training. Research training seminars are held monthly at the Clinical Research Facility. A student-run postgraduate society hosts monthly social meetings with careers-orientated talks.

Research Environment

In the UK Research Assessment Exercise 2008, the MMC, IGMM contributed to Unit of Assessment 4 (Hospital Based Clinical Subjects), which was ranked 1st out of 28 submissions by proportion of the highest possible 4* returns (40%) and by grade point average (3.2). The annual intake of PhD students at the IGMM is ~30, with currently ~100 in training. Over the last 6 years, 94% of students submitted within 4 years, with all but one being awarded a PhD.

What departmental and/or university resources will be made available to support the project?

Our PhD students have full access to all facilities and support services within the Molecular Medicine Centre. We are fully equipped for molecular and cell biology research, and expert in genetics, genomics, bioinformatics, proteomics, and imaging (see selected references).

1st Supervisor

Professor David Porteous is the Head of Medical Genetics Section and Director, Molecular Medicine Centre, Institute of Genetics and Molecular Medicine. He has supervised 21 PhDs to completion. He cloned DISC1 at the t(1;11) breakpoint in 2000, identified DISC1/2 and has contributed extensively to this research area ever since.

2nd Supervisor

Professor Andrew McIntosh is Chair of Biological Psychiatry and SFC Senior Clinical Research Fellow at The University of Edinburgh. He has authored more than 100 papers in the field of major mental illness and is PI on an MRC and a CSO Research Grant supporting the programme of using stem cells to model major psychiatric disorder.

Relevant background reading

1. Zhu H, Lensch MW, Cahan P, Daley GQ (2011) Investigating monogenic and complex diseases with pluripotent stem cells. Nature Reviews Genetics 12;266-75
2. Porteous D, Millar JK, Brandon NJ and Sawa A (2011) ‘DISC1 at 10: connecting psychiatric genetics and neuroscience’ Trends in Molecular Medicine, 17, 699-706.
3. Brown SM et al (2011). "Synaptic modulators Nrxn1 and Nrxn3 are disregulated in a Disc1 mouse model of schizophrenia." Mol Psychiatry 16: 585-7
4. Hennah W & Porteous D (2009). The DISC1 pathway modulates expression of neurodevelopmental, synaptogenic and sensory perception genes. PLoS ONE 4:e4906.
5. Clapcote SJ et al (2007). Behavioral phenotypes of Disc1 missense mutations in mice. Neuron 54: 387-402.
6. Millar JK et al (2005). DISC1 and PDE4B are interacting genetic factors in schizophrenia that regulate cAMP signaling. Science 310:1187-91.
7. Johnstone M, Thomson PA, Hall J, McIntosh AM, Lawrie, SM and Porteous DJ (2011) DISC1 in Schizophrenia: Genetic Mouse Models and Human Genomic Imaging. Schizophr Bull 37(1): 14-20
8. Sprooten E, Sussmann JE, Moorhead TW, Whalley HC, ffrench-Constant C, Blumberg HP, Bastin ME, Hall J, Lawrie SM, McIntosh AM (2011) Reduced white matter integrity in healthy individuals carrying the A-allele at DISC1 Ser704Cys Mol Psychiatry 16(7):685