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Understanding the consequences of ageing in adult stem cells

Primary Supervisor: Professor Jon Frampton, Institute of Cancer and Genomic Sciences

Secondary supervisor: Dr Rui Montiero

PhD project title: Understanding the consequences of ageing in adult stem cells

University of Registration: University of Birmingham

Project outline:

Adult organs are maintained by specialised stem cells that persist throughout life thanks to their ability to make exact copies of themselves, all the time retaining the ability to on demand produce the differentiated component cells of the tissue of which they are a part. The tight control of stem cell behaviour is critical in enabling them to function effectively and involves a complex interplay between internal mechanisms, largely involving the control of gene transcription, and external influences from the stem cell environment (‘niche’). Potentially, changes in both internal or external influences can underlie a decline in stem cell function with age.

Our laboratories are particularly interested in the ways in which inherited or acquired variations in the levels of critical stem cell transcription factors impact upon the aging of adult stem cells. The principal focus is upon those stem cells that maintain the supply of differentiated cells in the blood and the roles played by the transcription factor proteins MYB and GATA2. We are also interested in the extent to which such variations in transcription factor levels contribute to the phenotypic and functional heterogeneity of the total complement of stem cells in a tissue.

The overall experimental approaches to be used will include a combination of animal models (Zebrafish and mouse) that are amenable to genetic modification (generally editing using CRISPR-cas9) of genes thought to influence stem cell behaviour and can be investigated over the whole of their lifespan in a feasible timeframe. Studies on animal models will be complemented by work on human cell material when appropriate. Analyses of the consequences of variations in transcription factor function will include both in vivo and in vitro assays as well as a range of cellular and molecular approaches, often performed at the single-cell level, including both genome-wide (‘omics’) molecular measurements and flow cytometry-based assessments of phenotype and signalling. Omics methods will be used to assess the individual cell transcriptome (RNA-seq) and the regulation of gene activity as reflected in chromatin structure (ATAC-seq and ChIP-seq). The large data sets generated by the latter methodologies will require application of bioinformatic analysis, for which the student will receive training.

Studies on these features of adult stem cells are of both fundamental interest as well as having relevance to understanding how stem cell function can be compromised in later life. Such knowledge should provide insight into possible mitigations against age-related stem cell decline.

References:

  1. Aging of hematopoietic stem cells.de Haan G, Lazare SS. Blood. 2018 Feb 1;131(5):479-487. doi: 10.1182/blood-2017-06-746412. PMID: 29141947

BBSRC Strategic Research Priority: Understanding the Rules of Life: Stem Cells

        Techniques that will be undertaken during the project:

        • Gene editing (CRISPR-cas9) to create gene reporters and to modify gene function
        • Animal handling and monitoring
        • Tissue preparation and cell isolation (including cell sorting)
        • In vivo and in vitro assays of stem cell function (including transplantation assays and colony assays)
        • Cell analysis by fluorescence microscopy and flow cytometry
        • Omics methodology (including RNA-seq, ATAC-seq, and ChIP-seq)
        • Bioinformatic data analysis

        Contact: Professor Jon Frampton, University of Birmingham