Additional Supervisor: Carsten Daub [Karolinska Institutet]
Background
‘Liquid biopsy’, which includes the analysis of cell-free nucleic acids (cfNA), has been pioneered as a noninvasive method for diagnostics and precision medicine (Lo et al., 2021). In healthy and disease states, cell-free DNA (cfDNA) and cell-free RNA (cfRNA), are found in body fluids, representing the detritus of cell death. Recently developed molecular and computational methods can detect the tissue-of-origin of plasma cfDNA and cfRNA to inform disease states (Sadeh et al., 2021, Sevahn et al., 2022) and expand the clinical potential of ‘liquid biopsies’.
In critical illness, patients frequently present in multiple organ failure caused by a variety of pathologies. The acute and severe nature of the illness often causes diagnostic, therapeutic and prognostic challenges. Deciphering the pathophysiology is limited by inability to directly and contemporaneously biopsy relevant tissues. ‘Liquid biopsies’ offers a method to understand pathophysiology mechanisms in critical illness.
Using plasma cfDNA chromatin immunoprecipitation with sequencing (ChIP-seq) of modified histones, genome-scale information on tissue-of-origin and gene transcription can be obtained (Sadeh et al., 2021). This is based on histone methylation marks that identify tissue-specific gene regulation (Biddie et al., 2010). Similarly, circulating plasma cfRNA have been shown to contain mature transcripts that originate from multiple organs, and can be mapped to tissue-of-origin through computational deconvolution to inform disease states (Sevahn et al., 2022).
Interrogation of cfNAs can therefore provide mechanistic insight into critical illness. The possibility of detecting multiple tissue signals provides a whole-patient level of noninvasive ‘biopsy’ to understand critical illness associated with multiple organ failure.
Critically ill patients will be recruited as part of the LicuiD (Liquid biopsy In the Critically Unwell wIth acute Disease) study (PI: Dr Simon Biddie). Plasma samples will be collected for cfDNA and cfRNA from critically ill patients in intensive care with a variety of underlying acute illnesses, including myocardial infarct and kidney injury. Plasma samples will be used to generate cfDNA ChIP-seq and cfRNA-seq profiles. The integration of cfNA ‘omics’ approaches with clinical information will uncover pathophysiology mechanisms, with a goal to identify novel biomarkers and therapeutic targets towards precision medicine.
Aims
1. Identify tissue-specific transcriptomic and epigenomic signatures from cfNAs as a noninvasive method to determine pathological mechanisms in critical illness.
2. Identify disease-specific genes from cfNA transcriptomic and epigenomic datasets to discover novel mechanistic and therapeutic targets in critical illness.
3. Detect disease-specific transcription or epigenetic markers from cfNAs to inform potential diagnostic and / or prognostic biomarkers in critically ill cohorts.
Training Outcomes
The Project will develop knowledge and skills in molecular biology, genomics and computational biology using clinical samples. The project will involve molecular techniques related to RNA and DNA purification and library preparation for sequencing. A significant element of the project will involve development of computational skills to address the unique challenges associated with cfDNA and cfRNA omics data, integrated with clinical information.
Specific training outcomes are to:
1. Understand the molecular biology of tissue-specific gene regulation using cfNAs in health and disease.
2. Develop molecular skills (extraction, sequencing library preparation) of cfNAs from clinical samples.
3. Develop computational skills in transcriptomic analysis to identify tissue-specific signatures and gene-level phenotypes.
4. Design computational tools to address the multi-organ source of cfNAs.
Q&A Session
If you have any questions regarding this project, you are invited to attend a Q&A session hosted by the Supervisor(s) on 8th December at 11.30am via Microsoft Teams. Click here to join the meeting. If you get an error message when accessing the link, please try a different device.
About the Programme
This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.
All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.
Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the following link:
https://www.ed.ac.uk/usher/precision-medicine/app-process-eligibility-criteria
For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine
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