Omics in Disease Diagnosis and Therapy

Our new ‘thematic’ MCT Research Seminar Series was launched on November 8th with the opening talks on ‘Omics in Disease Diagnosis and Therapy’. The aim of the new format, with presentations spanning several research groups and diseases to facilitate knowledge exchange and foster cross-collaboration.

Dr Sudipto Das – Genomic and epigenomic approaches as a vital discovery platform

The talk broadly focused on various genomic and epigenomic platforms that have been established in the lab enabling us to interrogate the various alterations that underpin disease-associated features. Using specific clinical case examples, the talk demonstrated how the whole genome, exome and shallow sequencing have allowed us to further our understanding about atypical clinical presentation of known cancer types. Furthermore, the application of targeted methylation sequencing on FFPE tissue and it’s further utilization to stratify metastatic colorectal and heart failure patients using deep learning approaches was also explained.

Dr Katie Benson – Integrating Genomics into the Clinical Care Pathway

Next-generation sequencing is quickly replacing single gene tests in clinical practice. The integration of these genomic tests has been slow as a result of barriers including data processing and interpretation, handling of incidental findings, storage of data and access to genetics services and clinical geneticists. The Epilepsy Lighthouse project, building on the success of the epilepsy electronic patient record (EPR), has used eHealth technologies to facilitate the integration of genomics results into the epilepsy clinic. This has facilitated multidisciplinary team discussions of patients and their genomics results. As part of this project, we have sequenced 97 adult and paediatric Irish epilepsy patients and successfully provided a genetic diagnosis in 24% of cases.

Dr Chiara DeSanti – MicroRNA function in health and disease

Since the sequencing of the human genome back in 2001, non-coding RNAs have been shown to play a critical role in regulating gene expression at a transcriptional, post-transcriptional and translational level. Among the several classes of non-coding RNAs, our group is interested in microRNAs (miRNAs), small non-coding RNA molecules (18-25 nt in length) firstly discovered in C.elegans as negative regulator of gene expression through binding to the 3’untranslated region (UTR) of a target mRNA and inhibiting its translation and/or leading to mRNA degradation. MiRNAs expression was found altered in all human diseases so far, where they have been proposed as diagnostic/prognostic biomarkers and as key players in the pathogenic process itself due to their pleiotropic ability to bind hundreds of mRNAs simultaneously. Therefore, it’s hugely important to define true miRNAs::mRNAs interactions to understand their biological role and the pathways that they affect, in the overall aim of designing therapeutic strategies to enhance or block miRNAs. In order to do so, online target predictions is usually the first step, but experimental validation is needed to verify the in silico-predicted interaction. Several methods have been developed to address this issue, and they can be indirect (i.e. transcriptomic and proteomic changes are measured after over-expression/depletion of a miRNA), or direct (i.e. miRNA::mRNA complexes are captured and physical interactions are assessed, including the RCSI-developed method called miR-CATCH). Gold standard for the validation of high-throughput screening is the luciferase assay, again routinely used in several laboratories across the College. In our group, we are focussing on the role of miR-155 in macrophage polarisation in the context of multiple sclerosis (MS), a neurodegenerative disease where proinflammatory macrophages infiltrate the central nervous system and promote chronic inflammation and damage to myelin sheath. Our hypothesis, supported by preliminary data by our PI Dr MCoy and other researchers, is that miR-155 is promoting the proinflammatory state in macrophages and therefore blocking it would reduce inflammation and alleviate disease progression. Although proof of concepts for antimiR-155 therapy have been attempted in a mouse model of MS (EAE model), we are hoping to boost its efficacy by improving the delivery to macrophages of more stable versions of antimiR-155 or target-site blockers that minimise off-targets effects.