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October 3, 2016Supervisor View Full Details
October 11, 2016Email AddressEmail hidden; Javascript is required.
Webpage:http://pi.rcsi.ie/pi/dhenshall/index.asp
Research Field
- neuroscience and mental health
My WorkThe focus of the Henshall lab is understanding the causes and developing new treatments for the neurological disorder epilepsy. Our team uses multi-disciplinary approaches including genetics, cell and animal models, electrophysiology, molecular biology and imaging, as well studies in human brain tissue to explore the cell and molecular mechanisms of epilepsy development and we use novel pharmacologic and genetic approaches to manipulate key processes. Current projects include studies on epigenetic mechanisms coordinating gene expression and the role of non-coding RNAs such as microRNAs which fine tune the balance of protein levels in cells. We are also interested in the signalling pathways that control cross-talk between neurons and glial cells that underlies neuroinflammatory responses. On-going biomarker-focused research is exploring how circulating molecules such as microRNAs may reflect health and disease in epilepsy. For examples of recent published work by the laboratory see:
Gross C et al. Cell Rep in press (2016); Sebastián-Serrano Á et al. Hum Mol Genet (2016); Jimenez-Pacheco A et al. J Neurosci (2016); D'Orsi B et al J Neurosci (2016); Miller-Delaney S. Brain (2015)
Gross C et al. Cell Rep in press (2016); Sebastián-Serrano Á et al. Hum Mol Genet (2016); Jimenez-Pacheco A et al. J Neurosci (2016); D'Orsi B et al J Neurosci (2016); Miller-Delaney S. Brain (2015)
Outline of Potential Research projectsTargeting post-transcriptional control of gene expression for the treatment of genetic and developmental epilepsies.
Genetic and developmental epilepsies such as Dravet syndrome are devastating conditions affecting brain development and function. No specific treatments are available for patients and the seizures are often poorly controlled with current anti-epileptic drugs (AEDs). Thus, a deeper understanding of the disease mechanisms and novel treatment approaches are urgently required. Post-transcriptional mechanisms have recently emerged as important in several rare neurological diseases and in adult temporal lobe epilepsy. MicroRNAs are small non-coding RNAs that work post-transcriptionally to control (lower) protein levels. They do this by directly binding to complementary regions of target messenger RNAs. Some of the best-known targets of microRNAs in the brain control the structure and function of synapses where neurotransmission takes place. We have previously identified a number of microRNAs that are uniquely altered in the brain of adult patients with epilepsy and shown in experimental models that these can be targeted to produce potent effects on seizures.
This PhD project will explore the role of brain-expressed microRNAs in experimental models and patients of developmental and genetic epilepsies. The objective will be to characterize the microRNAs in experimental models and human samples. Next, studies will explore how levels of the microRNAs can be selectively manipulated in specific cell types in the brain. Finally, experiments will test how this affects neuronal network function and seizures and explore the mechanisms by which these effects are produced. The researcher will use a range of experimental techniques including RNA sequencing to characterize microRNA levels tissue and patient-derived iPS cells, assess biofluid microRNA levels as biomarkers of disease and response to therapy, and analyse the functional effects of targeting microRNAs using pharmacological and genetic approaches such as CRISPR-Cas9. These studies will provide training and expertise with gene expression profiling, the biochemistry of noncoding RNAs, gene editing techniques, antisense oligonucleotides, brain imaging, electroencephalography (EEG) and analysis of clinical data. Together, this research will explore new directions in the treatment and prevention of genetic and developmental epilepsies.
Genetic and developmental epilepsies such as Dravet syndrome are devastating conditions affecting brain development and function. No specific treatments are available for patients and the seizures are often poorly controlled with current anti-epileptic drugs (AEDs). Thus, a deeper understanding of the disease mechanisms and novel treatment approaches are urgently required. Post-transcriptional mechanisms have recently emerged as important in several rare neurological diseases and in adult temporal lobe epilepsy. MicroRNAs are small non-coding RNAs that work post-transcriptionally to control (lower) protein levels. They do this by directly binding to complementary regions of target messenger RNAs. Some of the best-known targets of microRNAs in the brain control the structure and function of synapses where neurotransmission takes place. We have previously identified a number of microRNAs that are uniquely altered in the brain of adult patients with epilepsy and shown in experimental models that these can be targeted to produce potent effects on seizures.
This PhD project will explore the role of brain-expressed microRNAs in experimental models and patients of developmental and genetic epilepsies. The objective will be to characterize the microRNAs in experimental models and human samples. Next, studies will explore how levels of the microRNAs can be selectively manipulated in specific cell types in the brain. Finally, experiments will test how this affects neuronal network function and seizures and explore the mechanisms by which these effects are produced. The researcher will use a range of experimental techniques including RNA sequencing to characterize microRNA levels tissue and patient-derived iPS cells, assess biofluid microRNA levels as biomarkers of disease and response to therapy, and analyse the functional effects of targeting microRNAs using pharmacological and genetic approaches such as CRISPR-Cas9. These studies will provide training and expertise with gene expression profiling, the biochemistry of noncoding RNAs, gene editing techniques, antisense oligonucleotides, brain imaging, electroencephalography (EEG) and analysis of clinical data. Together, this research will explore new directions in the treatment and prevention of genetic and developmental epilepsies.