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Professor Derek Blake

Professor of Neuroscience, Division of Psychological Medicine and Clinical Neurosciences

School of Medicine

Email
blakedj@cardiff.ac.uk
Telephone
+44 (0)29 2068 8468
Campuses
2.52, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ
Comment
Media commentator
Users
Available for postgraduate supervision

Overview

My research is focussed on the molecular basis of a range of inherited disorders (eg. neurodevelopmental syndromes and muscular dystrophies) that affect the brain and striated muscle. I use a range of molecular biology techniques to determine the cellular function of proteins involved in the aforementioned disorders. I am particularly interested in the effects of mutations and polymorphisms on protein function since these studies can identify underlying pathologies and potential therapies. We also use functional genomics and proteomic techniques to study disease mechanisms in common, polygenic disorders including schizophrenia, Alzheimer's disease and Fuchs' endothelial corneal dystrophy (FECD).

Biography

Publications

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Teaching

Bioinformatics (MSc) - Introduction to Bioinformatics

Medicine (MBBCh) - Case Based Learning (CBL) Facilitator

Medicine (MBBCh) - Platform for Clinical Sciences Tutor

Medical Pharmacology (BSc) and Biological Sciences (BSc) - Profession Training Year (PTY) supervisor

Transcription factors in neurodevelopmental disorders

Recent advances in neuropsychiatric genetics have identified biological processes and risk variants that are regulated by key schizophrenia-associated transcription factors (TFs) and chromatin writers (collectively transcriptional regulators) that are also causally implicated in a range of neurodevelopmental disorders through rare, exonic mutations. For many common disorders, altered binding of transcriptional regulators to non-coding variants can directly mediate disease risk, modulate gene expression and ultimately shape phenotypes. The major aim of this project is to define the genomic targets for selected schizophrenia-associated transcriptional regulators such as TCF4 (Transcription Factor 4) in cell models and tissue two differentiated human using chromatin-immunoprecipitation and next generation sequencing (ChIP-seq). In collaboration with Dr Matt Hill (https://www.cardiff.ac.uk/people/view/62738-hill-matt), we have used the near base-pair resolution of ChIP-seq to discover regulatory binding sites in genomic loci associated with schizophrenia and other common neurodevelopmental disorders and derive binding-site motifs for each TF where appropriate (https://orca.cf.ac.uk/107566/1/sbx164.pdf). We are also interested in Pitt-Hopkins Syndrome (PTHS) - a rare neurodevelopmental disorder caused by heterozygous TCF4 mutations. We are currently trying to determine the role of PTHS-associated mutations on the function of TCF4 in a range of model systems.

 

TCF4 in Fuchs' endothelial corneal dystrophy (FECD)

The cornea, the clear window at the front of the eye, is one of the most transplanted tissues worldwide with nearly 50,000 corneal grafts performed in 2015 in the USA alone. FECD affects approximately 4% of people over the age of 40 and is the most common indication for corneal graft surgery in the USA. Over time, cell loss and painful blistering cause changes in the transparency of the cornea and progressive loss of vision leading to blindness in the most severe cases. FECD is an inherited condition with approximately 80% of cases being associated with trinucleotide repeat expansion in an intron of the TCF4 gene. As described above, TCF4 has a regulatory function and can act as a molecular switch to turn other genes on and off by binding to specific sites in the genome. In collaboration with Prof Andrew Quantock (https://www.cardiff.ac.uk/people/view/38248-quantock-andrew) and Dr Matt Hill, we have shown that small alterations in the levels of TCF4 can have dramatic effects on cell function and cell survival. To improve our understanding of the molecular basis for FECD and to find new drug targets to treat this disorder, we are using the latest genetic techniques and cell models to identity the genes and processes that are controlled by TCF4 in corneal endothelial cells.

Microglial biology

The majority of risk genes for Alzheimer’s Disease (AD) are highly expressed in microglia - a specialized population of resident macrophage-like cells found in brain. Genetic risk for AD is concentrated in specific macrophage and microglial transcriptional networks that are regulated by a handful of transcription factors (TFs) including PU.1 and MEF2C. In collaboration with Dr Matt Hill (https://www.cardiff.ac.uk/people/view/62738-hill-matt), we are studying how these TFs regulate gene expression and AD risk using proteomic and genomic techniques. We are also using proximity-labelling proteomics to study the function of selected genes that form part of the AD-risk network in microglia. These projects will provide mechanistic insights into the molecular process involved in AD pathogenesis and will be used to find new drug targets to treat this disorder.

Organisation of the junctional sarcoplasmic reticulum (jSR) in striated muscle 

The jSR is a specialised region of the sarcoplasmic reticulum of muscle cells that concentrates resident and peripheral proteins to regulate calcium release and excitation-contraction coupling. To understand how the jSR is assembled we used immunoaffinity purification and mass spectrometry to identify proteins complexes that are targeted to the jSR in cardiac and skeletal muscle. We found that the myospryn complex interacts with ryanodine receptors (the major calcium release channel of the SR) and other components of the jSR in cardiac muscle (https://www.nature.com/articles/s41598-017-06395-6). We are currently using a range of molecular tools to understand the role of the myospryn complex during the assembly of jSR and how these processes are altered in heart disease.

Areas of expertise

Research links