The primary objective of the Institute of Diabetes and Regeneration Research (IDR) at the Helmholtz Zentrum München is to develop regenerative therapeutic approaches to treat diabetes mellitus. We provide an international environment and stimulating atmosphere in an institute dealing with various aspects of beta cell biology.
Diabetes mellitus is a complex and multifactorial disease characterized by progressive loss or dysfunction of the insulin-producing beta cells in the pancreas. Nowadays, no current treatments can stop or reverse the disease progression except bariatric surgery and islet transplantation. However, donor shortage and risks associated with life-long immunosuppression demand the development of alternative therapies. Therefore, intensive efforts in the field of diabetes research are put into the development of novel therapeutic approaches. ß cells are currently the prime target for cell-replacement and regenerative therapy. Triggering endogenous beta cell regeneration is a promising approach to restore beta cell mass and normoglycemia in diabetic patients. Beta cells are heterogeneous and differ in their glucose responsiveness, proliferative activity, maturation state, responsiveness to nutrient cues or even in the susceptibility to autoimmune attack in T1D as demonstrated by us and other labs (Bader, Migliorini et al., Nature, 2016; Bakthi et al., Nat Rev Endocrinol, 2019; Theis and Lickert, Nature, 2019). Thus, to identify and target distinct beta cell subpopulations with regenerative potential it is crucial to decipher beta cell heterogeneity and identify druggable targets and pathways.
Deciphering mechanisms of beta cell heterogeneity and regeneration
The overall goal of the project is to identify novel pathways and molecular targets to directly target specific beta cell populations to proliferate and/or mature in vivo to regenerate functional beta cell mass.
The proposed project aims:
i) to better understand the molecular mechanisms driving beta cell maturation and establishment and maintenance of beta cell heterogeneity
ii) to decipher and compare the molecular mechanisms underlying beta cell dysfunction and loss in type 1 and type 2 diabetes (e.g. extent of beta cell dedifferentiation in T1D and T2D)
iii) to analyze the targets and pathway of dedifferentiated, immature and mature beta-cells to have intervention points for beta-cell protection and regeneration
This project will be a collaboration with the MacDonald Islet Biology laboratory at the Alberta Diabetes Institute (www.bcell.org), which will focus on the functional assessment of beta cell heterogeneity and regeneration.
The PhD candidate will work with mouse, pig and human models (healthy, T1D and T2D) and employ cutting edge technologies, such as single-cell RNAseq, single-molecule RNA FISH, high-resolution imaging and CRISPR/Cas9 genome editing and phenotype analysis in vitro and in vivo.