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MRC Industrial CASE Studentship: Understanding Mechanisms of Beta-Cell Dysfunction using Genome Engineering in Patient-Derived Induced Pluripotent Stem Cells

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  • Full or part time
    Dr Gloyn
    Dr Beer
  • Application Deadline
    No more applications being accepted

Project Description

The ability to reprogram any patient cell type to pluripotency, as is the case with induced pluripotent stem cells (iPSCs), provides an important solution to the unmet need for more physiologically-relevant diabetes cell models. For example, when coupled with targeted in vitro differentiation protocols, these cells can be used to generate endocrine pancreas lineage cells accurately recapitulating both normal physiology, as well as the dysfunction observed in diabetes patients. Likewise, the tandem development of genome engineering technologies such as CRISPR-Cas9 means that not only are we able to study gene function in an endogenous expression context, but we can also introduce and correct diabetes-causing genetic perturbations into defined regions of the genome. The aim of this MRC-funded CASE studentship is to utilise iPSC-derived cell models harbouring both naturally occurring and artificially-introduced mutations from individuals with extreme diabetes phenotypes, so as to investigate mechanisms underlying pancreatic beta-cell failure. Initially, mutations in the insulin (INS) gene which cause monogenic forms of diabetes (neonatal and maturity-onset diabetes of the young) will be used as a tool to probe the effects of aberrant gene regulation and defective protein processing on beta-cell function. The techniques for studying these pathologies are also directly translatable to more complex forms of diabetes; the endoplasmic reticulum (ER) stress and beta-cell apoptosis observed in some INS -MODY individuals and Akita mice are also proposed to occur in type 2 diabetes (T2D).

Students on Industrial CASE Studentships carry out their research with co-supervision from RDM and an industrial partner. This gives students the opportunity to experience both an academic and an industrial research environment during their DPhil. Students will spend a minimum of three months working at the premises of the industrial partner during their four year project.

The successful candidate will capitalise upon extensive skills in genome engineering and cellular phenotyping, as well as access to clinical data, diabetes patients, and primary human tissue, at the University of Oxford. This will be coupled with skills and expertise in iPSC culture and differentiation at Novo Nordisk. Specifically, the candidate will:
- Generate iPSC lines harbouring monogenic diabetes mutations (affecting INS regulation and expression, as well as ER stress and beta-cell apoptosis)
- Use in vitro differentiation protocols to push these mutated cells down the endocrine pancreas lineage
- Characterise mutant cells using extensive phenotypic assays, and compare directly to data from wild-type cells and primary human tissue
- Use these diabetes patient, endocrine pancreas-relevant cells in small molecule/compound screens aiming to alleviate the observed pathophysiology (for example by stabilising the INS transcript, or up-regulating molecular chaperones)
- Translate these data and models into pipelines for studying more complex forms of beta-cell dysfunction, as occurs in T2D

Supervision at Novo Nordisk will be provided by Dr Matthias Hansson and Dr Christian Honoré.

Funding Notes

This project is directly funded through an MRC Industrial CASE Studentship. For UK residents, funding covers all fees, a stipend of at least £16,057 per year, travel to/from the premises of the industrial partner, expenses incurred by the student while working at the premises of the industrial partner and a contribution towards conference attendance. For other EU citizens, funding covers fees, travel and additional expenses but no stipend is provided. Note, if you fall outside these categories, funding would be subject to approval by the funding body.

References

FLANNICK J, THORLEIFSSON G, BEER NL, JACOBS SB, GRARUP N, BURTT NP, MAHAJAN A, FUCHSBERGER C, ATZMON G, BENEDIKTSSON R, BLANGERO J, BOWDEN DW, BRANDSLUND I, BROSNAN J, BURSLEM F, CHAMBERS J, CHO YS, CHRISTENSEN C, DOUGLAS DA, DUGGIRALA R, DYMEK Z, FARJOUN Y, FENNELL T, FONTANILLAS P, FORSÉN T, GABRIEL S, GLASER B, GUDBJARTSSON DF, HANIS C, HANSEN T, HREIDARSSON AB, HVEEM K, INGELSSON E, ISOMAA B, JOHANSSON S, JØRGENSEN T, JØRGENSEN ME, KATHIRESAN S, KONG A, KOONER J, KRAVIC J, LAAKSO M, LEE JY, LIND L, LINDGREN CM, LINNEBERG A, MASSON G, MEITINGER T, MOHLKE KL, MOLVEN A, MORRIS AP, POTLURI S, RAURAMAA R, RIBEL-MADSEN R, RICHARD AM, ROLPH T, SALOMAA V, SEGRÈ AV, SKÄRSTRAND H, STEINTHORSDOTTIR V, STRINGHAM HM, SULEM P, TAI ES, TEO YY, TESLOVICH T, THORSTEINSDOTTIR U, TRIMMER JK, TUOMI T, TUOMILEHTO J, VAZIRI-SANI F, VOIGHT BF, WILSON JG, BOEHNKE M, MCCARTHY MI, NJØLSTAD PR, PEDERSEN O, GO-T2D CONSORTIUM, T2D-GENES CONSORTIUM, GROOP L, COX DR, STEFANSSON K, ALTSHULER D. 2014. Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat. Genet., 46 (4), pp. 357-63.
FLANNICK J, BEER NL, BICK AG, AGARWALA V, MOLNES J, GUPTA N, BURTT NP, FLOREZ JC, MEIGS JB, TAYLOR H, LYSSENKO V, IRGENS H, FOX E, BURSLEM F, JOHANSSON S, BROSNAN MJ, TRIMMER JK, NEWTON-CHEH C, TUOMI T, MOLVEN A, WILSON JG, O'DONNELL CJ, KATHIRESAN S, HIRSCHHORN JN, NJØLSTAD PR, ROLPH T, SEIDMAN JG, GABRIEL S, COX DR, SEIDMAN CE, GROOP L, ALTSHULER D. 2013. Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes. Nat. Genet., 45 (11), pp. 1380-5.
BEER NL, TRIBBLE ND, MCCULLOCH LJ, ROOS C, JOHNSON PR, ORHO-MELANDER M, GLOYN AL. 2009. The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum. Mol. Genet., 18 (21), pp. 4081-8.

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