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Understanding kidney development and disease using human pluripotent stem cells

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Pluripotent stem cells (PSP) can form all tissues of the body and have excellent potential as agents for tissue regeneration. Our laboratory as part of the North West Embryonic Stem Cell Centre (NWESCC) has generated a number of human embryonic stem cells (hESC) lines and several induced pluripotent stem cells (iPSCs) (1,2) from human somatic cells using plasmid viral or other reprogramming methods to introduce the conventional ‘Yamanaka factors (3). We have focused on differentiation of PSCs to mesodermal lineages (1). Recently several new protocols have been developed to generate cells of the major renal lineages (giving glomerular and collecting tubule structures)(4). Since kidney disease is a major problem for health services it may be possible to develop disease specific models from pluripotent stem cells differentiated to kidney progenitors. These could be used to help understand kidney disease and to develop new drugs/treatments for disease. One group of patients are those with ‘renal cysts and diabetes syndrome’ caused by heterozygous HNF1β mutations. Prof Woolf has identified 15 families with proven mutations in this gene(5). The student will derive iPSCS from patient/normal skin fibroblasts or blood cells. Using protocols developed in the lab he/she will differentiate them to ureteric epithelium. Differentiation to kidney progenitors will be compared to wild type iPSCs and hESCs. The mutation will be corrected using gene editing technologies (Crispr-Cas) to prove that the phenotypic differences are a result of the mutation rather than genetic variation. IPSC-ureteric bud organoids will be cultured under conditions which promote cysts development to compare to non-mutant cells. Once the model is established, cells will be manipulated using knockdown/inhibitors to understand more about why the HNF1β mutation causes renal cysts. Techniques will include hESC/iPSC culture/differentiation, immunofluorescence, Western blotting, microarray analysis, confocal microscopy, flow cytometry, quantitative RT-PCR, genetic manipulation and gene editing technologies.

Funding Notes

This project has a Band 2 fee. Details of our different fee bands can be found on our website. For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website. Informal enquiries may be made directly to the primary supervisor.

References

Cheng A, Kapacee Z, Peng J, Lu S, Lucas R, Hardingham TE, Kimber SJ. (2014) Cartilage Repair Using Human Embryonic Stem Cell-derived Chondroprogenitors. Stem Cells Translational Medicine.

McKay TR, Camarasa MV, Bates N, Fitzsimmons J, Brison, DR, Aplin, JD & Kimber SJ (2011) Generation of continuous immortalised human placental feeders suitable for maintenance of human embryonic stem cells using lentiviral constructs containing BMI and hTert. Stem Cell Research 7,154-162.

Yamanaka, S. & Blau H.M. (2010) Nuclear reprogramming to a pluripotent state by three approaches. Nature 2010, 465, 704-712.

Takasato M, Er PX, Becroft M, Vanslambrouck JM, Stanley EG, Elefanty AG & Little MH (2013)Directing human embryonic stemcell differentiaon towards arenal lineage generates a sielf orgnaising kidney Nature VCell Biol 16,118-126.

Kolatsi-Joannou M Bingham C, Ellard S, Bulman MP, Allen LIS, Hattersley AT , Woolf AS (2001) Hepatocyte nuclear factor-1β: a new kindred with renal cysts and diabetes and gene expressionin normal human development. J Am Soc Nephrol 12, 2175-2180

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