solimena group
Peter Hoboth
TRAFFICKING OF INSULIN SECRETORY GRANULES/
CELL BIOLOGY OF INSULIN GRANULE AGEING
The regulated secretion of the insulin hormone by pancreatic beta cells, in particular, is critical for control of glucose homeostasis in vertebrates. In humans, and in mammals in general, the release of insulin, which follows the elevation of blood glucose levels, occurs in two sequential phases. The prevailing current model indicates that beta cells store insulin in two distinct pools of insulin secretory granules (ISGs). The readily releasable pool is represented by ISGs that are docked at the plasma membrane and can immediately undergo exocytosis upon glucose-induced depolarization of the beta cell plasma membrane. The reserve pool comprises ISGs that are further away from the plasma membrane and may be recruited for exocytosis upon consumption of the first pool. The loss of the first-phase of glucose-stimulated insulin secretion is a hallmark of type II diabetes.
It has been described that newly assembled ISGs are preferentially recruited for exocytosis in comparison to older granules; however, no information is available about the molecular processes involved in the aging of insulin granules. For microtubule-dependent transport of ISGs from trans-Golgi network is responsible conventional kinesin, whereas for interaction with cortical actin meshwork is necessary another molecular motor, myosin 5A. Several lines of evidence suggest that small GTPases Rab 3A and Rab 27A, its effector proteins Slac2c/MyRIP, Slp4/Granuphilin are involved in the regulation of ISGs transport.
The aim of my project is to characterize the age-dependent trafficking of newer versus older ISGs on the molecular level and possibly reconstitute this transport process in vitro. To address these questions, differential labeling of ISGs in cell cultures, selective knockdown or using of mutated genes, pharmacological approach, live-cell imaging using TIRF microscopy and in vitro motility assays will be employed.
Contact details:
peter.hoboth {at}
mailbox.tu-dresden.de
+49 (0)351 458.6679