Research

 

We have the following major research projects:

1.    A stem cell differentiation approach to study development of diabetes and pancreatic disease

Diabetes mellitus is a disease of major significance to human world health, with an increasing prevalence (Steinbrook 2006) and a considerable macroeconomic burden (Yach et al. 2006). Most forms of diabetes, including type 1 (T1D), type 2 diabetes (T2D), and monogenic diabetes, have in common an insufficient insulin secretion from the pancreatic β-cells (Fajans et al. 2001; Lyssenko et al. 2008) ultimately leading to insulin dependence and hence the need of symptomatic insulin treatment.   In Norway there are 28 000 diabetes patients with insulin-dependent diabetes (Strom et al. 2014).

MODY families

mody

Patients from families with monogenic diabetes (MODY, maturity-onset diabetes of the young) provide an excellent opportunity to study molecular events at protein level both before and after the onset of the clinical manifest disease. MODY is caused by pancreatic beta cell dysfunction due to a single germ line mutation in genes involved in transcriptional regulation in pancreatic beta cells. More than 90 % of MODY mutation carriers ultimately develop diabetes; non-diabetic family members are therefore assumed to be in a pre-diabetic state (Fajans et al. 2001). The advantage of studying MODY patient-derived samples lies in the monofactorial/monogenic origin of the disease, and the absence of the immune attack (unlike type 1 diabetes) and insulin resistance (unlike type 2 diabetes) allowing an unambiguous characterization of regulatory mechanisms. Secondly, the heredity transmission of the disease allows the use of healthy family members as controls, as such reducing the risk of genetic background interference. To date, 14 MODY genes have been described  The efficacy of sulfonylurea drugs to treat both some MODY forms (Pearson et al. 2003) and type 2 diabetes (Morsink et al. 2013) exemplifies that at least some underlying molecular mechanisms are shared between different diabetes forms, and a treatment strategy for MODY may be valid for diabetes patients in general.

Induced pluripotent stem cells (iPSCs) and their potential for diabetes therapy

With the discovery of induced pluripotent stem cells (iPSC) in 2006 and the subsequent possibility to direct iPSC into becoming islet-like cells, several promising clinical efforts are under way to provide patients with autologous islet-like cells (iPSC-based) or allogenic islet-like cells (hESC, human Embryonal Stem Cells) from unlimited source. Notably hESC-based β-cell progenitors are in clinical Phase 1/2 trials since 2014 with Viacyte Inc. (Pepper et al. 2017), but capsular fibrosis poses a challenge. T1D iPSC-derived β- like cells have been generated and studied in a narrow clinical context (Millman et al. 2016). Current research challenges in the replacement field include improvement of differentiation protocols to obtain functional β- cells, encapsulation strategies and immune modulation of allogenic treatments .

Goal A: Generation and characterization of iPSC-derived pancreatic progenitor cells and mature beta cells from MODY patients.

Goal B: Proteomics and functional profiling of MODY patient cell models to identify and validate candidate signaling pathways.

Goal C: MODY mutation repair and characterization of rescued beta cells.

 

2.   Adrenogonadal systems medicine  – Precision medicine in testicular and ovarian and adrenal cortical failure or overproduction due to adreno-gonadal developmental disorders

The term hypogonadism encompasses the functional failure of testes in male subjects and ovaries in female subjects, usually divided into hypergonadotropic (i.e. elevated FSH and LH levels) and hypogonadotropic (i.e. inappropriately normal FSH and LH levels) hypogonadism. We focus our reserarch on conditions associated with hypergonadotropic hypogonadism primarily affects ovaries (Turner syndrome, autoimmune ovary disease, chemo- or radio-therapy, disorders of sexual development (DSD)), or testes (Klinefelter syndrome, chemo- or radio-therapy, DSD, orchitis) and female hyperandrogenism, including polycystic ovarian syndrome and congenital adrenal hypoplasia.

Goal A: Contribute to developing new precision medicine-based (personalized) classification of gonadal (testicular and ovarian) disease, by defining new subgroups.

Goal B: Develop new precision medicine-based (personalized) diagnostic and prognostic tools to detect subgroups of hypo or hyper-gonadal disease (with or without adrenocortical disease) and risk factors for gonadal tumors

Goal C: Contribute to the development of precision medicine-based (personalized)  therapies in hypogonadal and hypergonadal disease.

Collaborators:

Frode Berven – Institute of Biomedicine, UiB

Laurence Bindoff – Dept. of Clinical Medicine, UiB

Kamal Mustafa – Dept. of Clinical Dentistry, UiB

Inge Jonassen – Computational Biology Unit, UiB

Tor Paaske Utheim – Dept. of Medical Biochemistry, Oslo University Hospital, UiO

Rohit Kulkarni – Joslin Diabetes Center of Harvard Medical School, USA

Steve Gygi – Harvard Medical School, USA

Bridget Wagner – Broad Institute of MIT, USA

Adrian Teo – Nanyang Technological University, Singapore

Paul Gadue – University of Pennsylvania, USA

Ludovic Vallier – Wellcome Trust Medical Research Council of Cambridge Stem Cell Institute, UK

Pedro Herrera – Dept. of Genetic Medicine and Development
, University of Geneva, Switzerland

Alfred Vertegaal – Leiden University Medical Center, Netherlands