Ruprecht-Karls-Universität Heidelberg
HBIGS homepage | Forgot password
Korff_Arnold0118 - Scientist (f/m) / PhD position
Project no:
Korff_Arnold0118

Project leader:

Project supervisor:
Korff, Thomas
Application deadline:
13. Jan 2019
Start of PhD project:
1. Feb 2019

Project description:

Title:
RGS16-dependent phenotype regulation of arterial vascular smooth muscle cells
Summary:
Our work group (AG Arnold) grants a professional and individual supervision of PhD students and provides a stimulating atmosphere within a team of young and enthusiastic scientists. The work program of this project comprises application of a wide range of cutting-edge techniques which guarantees a high level of scientific training. We also offer in-house methods seminars for advanced training and support participation in national and international scientific meetings. Our two-week progress reports ensure that the candidate will broaden their theoretical and practical knowledge and independent research skills. Detailed information about our group can be obtained from the institute’s website http://www.medizinische-fakultaet-hd.uni-heidelberg.de/Mitarbeiter-HKP.110917.0.html

A pivotal feature of arteries is their capacity to adapt the architecture of the vascular wall to alterations in the microenvironment. Vascular smooth muscle cells (VSMCs) control pivotal properties of the arterial vessel wall. Depending on their phenotype, these cells may regulate the contraction/dilation of blood vessels or drive structural and functional changes in the vessel wall as a result of hypertension, arteriosclerosis or arteriogenesis. Wall stress or biomechanical stretch as a common trigger of these vascular remodeling processes is sufficient to control the switch from the contractile to the synthetic SMC phenotype that is a prerequisite for adaptive modifications in the arterial vessel wall. In this context, G-protein activity and signaling is a limiting factor for signal transduction of both kinds of stimuli to orchestrate phenotype changes of arterial VSMCs. G-protein activity itself is controlled by an endogenous protein family known as “regulators of G-protein signaling” (RGS). We have previously shown that loss of RGS5 in vivo prevented both flow-induced (arteriogenesis) as well as hypertension-induced arterial remodeling in mice as well as RhoA activation. Furthermore, hypertension also induced RGS16 expression – a functional homologue to RGS5 – which was further increased in the absence of RGS5. Interestingly, RGS5 and RGS16 both have the ability to inhibit Gαq/11 and Gαi/o subunits but differ in their affinity. The future experimental approaches aim at exploring the regulation and functional contribution of RGS16 to G-protein- and hypertension-induced VSMC responses and arterial remodeling.
References:
Arnold C., Feldner A., Pfisterer L., Hödebeck M., Troidl K., Genové G., Wieland T., Hecker M., Korff T, RGS5 promotes arterial growth during arteriogenesis, EMBO Mol Med. 2014 Jun 27;6(8):1075-89.
doi:10.15252/emmm.201403864.

Arnold C, Demirel E, Feldner A, Genové G, Zhang H, Sticht C, Wieland T, Hecker M, Heximer S, Korff T, Hypertension-evoked RhoA activity in vascular smooth muscle cells requires RGS5, FASEB J. 2018 Jan 5:fj201700384RR
Methods that will be used:
Our experimental portfolio includes multiple established, state-of-the-art in vitro, ex vivo and in vivo techniques. Besides standard methods (qPCR, immunofluorescence imaging, confocal microscopy, Western blot, immunoprecipitation), we use vessel perfusion models, spheroid assays and 3D organoid cultures. In vivo, we utilize several surgical mouse models which allow for quantitative assessment of vascular remodeling processes such as arteriogenesis, neointima formation or hypertension-induced arterial remodeling in RGS16-deficient mice. To unravel the mechanisms by which RGS16 controls cellular functions microarray and proteome profiling techniques will be applied.
Cooperation partners:
Nina Wettschureck (Bad Nauheim), Scott Heximer (Toronto, Canada), Thomas Wieland (Mannheim), Rudolf Schubert (Mannheim), Kirk Druey (USA)
Personal qualifications:
Successful PhD candidates should be ambitious, highly motivated and enjoy teamwork in a team of competitive young scientists. The PhD candidate should take a great interest in life sciences, molecular biology as well as physiology and be creative to apply this knowledge to develop new hypotheses. The successful candidate will be tightly supervised by the PI, should be able to work independently and also enjoy interaction and discussion with other scientists. A good background in standard molecular biological methods is expected. Experience with animal handling (FELASA B certificate or equivalent) would be beneficial but is not mandatory for application.
Keywords:
G-protein signalling, vascular smooth muscle cells, vascular remodeling, preclinical research, vascular function