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(A*STAR) Elucidation of molecular footprints of kidney fibrosis through integrative ‘omics’-based analysis


Project Description

The fibrosis is a common pathway of structural damage in many kidney diseases. It is usually diagnosed when patients present with an irreversible drop in glomerular filtration rate. The progress in management of kidney fibrosis has been slow because of the limited understanding of its molecular phenotype. The key ambition of this project is to reduce this barrier by providing insights into the intra-renal mechanisms leading to kidney fibrosis and the discovery of its molecular footprints that could be developed further into new bio-markers. An early detection of fibrosis would open a window of opportunity to slow/prevent the progression of kidney disease prior to a decline in kidney function.

The project will build up on our experience in genomics, transcriptomics, epigenomics, bioinformatics and gene editing. We will apply the current state-of-the-art methods of transcriptome quantification and DNA methylation profiling to characterise the transcriptional and epigenetic programmes of kidney fibrosis and identify its molecular signatures. The identified footprints of kidney fibrosis will be integrated with available functional annotations of biologically active elements of the human genome. We will use high-throughput chromosome conformation capture (Hi-C) to examine the interactions of linearly distant domains of relevance to kidney fibrosis that are brought into physical contact through DNA looping. In the final stage of the project we will use CRISPR/Cas9-based strategy to selected kidney regulatory DNA targets to examine how their edition affects activation/repression of kidney gene expression in vitro.

The outcomes from this project will determine molecular footprints of kidney fibrosis fostering the development of new diagnostic tests, tailored therapeutic strategies and paving the way to precision medicine for structural kidney damage.

Entry Requirements:
Applications should be submitted online and candidates should make direct contact with the Manchester supervisor to discuss their application directly. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is available to UK/EU candidates. Funding covers fees (UK/EU rate) and stipend for four years. Overseas candidates can apply providing they can pay the difference in fees and are from an eligible country. Candidates will be required to split their time between Manchester and Singapore, as outlined on View Website.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. Xu X, et al. Molecular insights into genome-wide association studies of chronic kidney disease-defining traits. Nature Communications 2018;9:4800.
2. Papakrivopoulou E, et al. Vangl2, a planar cell polarity molecule, is implicated in irreversible and reversible kidney glomerular injury. Journal of Pathology 2018;246:485-496.
3. Pickard A, Adamson A, et al. Collagen assembly and turnover imaged with a CRISPR-Cas9 engineered Dendra2 tag. 2018, BioRxiv (https://www.biorxiv.org/content/early/2018/06/05/331496)
4. See K, et al. Single cardiomyocyte nuclear transcriptomes reveal a lincRNA-regulated de-differentiation and cell cycle stress-response in vivo. Nature Communications 2017;8:225.
5. Lee D, et al. Gene neighbourhood integrity disrupted by CTCF loss in vivo. 2018, BioRxiv (https://www.biorxiv.org/content/early/2017/09/12/187393)

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