Ruprecht-Karls-Universität Heidelberg
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Augustin0218 - Scientist (f/m) / PhD position
Project no:
Augustin0218

Project leader:

Project supervisor:
Augustin, Hellmut G.
Application deadline:
31. Oct 2018
Start of PhD project:
1. Nov 2018

Project description:

Title:
Mechanisms of vascular maturation and quiescence during development, homeostasis and aging
Summary:
Healthy blood vessels are vital for human health. In fact, vascular dysfunction is directly or indirectly responsible for at least 70% of all cases of human mortality. The pathophysiological consequences of endothelial cell (EC) dysfunction have therefore made EC and activation-associated EC gene products an attractive target for therapeutic intervention. Yet, the focus on EC activation programs has contributed to portraying EC as a bradytrophic cell population with limited turnover within months to years that engages actively in major physiological processes only upon exogenous cytokine activation. This may be among the most severe misconceptions of the field of vascular biology. Instead, EC should likely be viewed as a dynamic cell population that differentiates in an organotypic fashion and whose quiescent phenotype needs to be actively maintained by cell autonomous and paracrine-acting mechanisms.

Our laboratory is taking a radically different approach to study blood vessel function during health and disease by focusing on vascular maturation and quiescence as actively controlled molecular processes. Employing a combination of genome-wide systems biology approaches with molecular and functional study of individual candidate molecules in conditional gene targeting approaches in vivo and in vitro, work in our laboratory is aimed at shedding fundamental insights into blood vessel functions that control important homeostatic and disease-related pathobiological processes.

We now have within the ERC Advanced Grant “Angiomature” and other extramurally funded projects up to 5 open PhD positions, for which we are recruiting talented and highly motivated students who want to make important contributions to above outlined research directions in order to lay a solid foundation for a later career in the life sciences.
References:
Singhal S#, Liu X#, Inverso D, Jiang K, Dai J, He H, Bartels S, Li W, Abdul Pari, AA, Gengenbacher N, Besemfelder E, Hui L, Augustin HG*, Hu J*: Endothelial cell fitness dictates the source of rege¬ne¬rating liver vasculature. J Exp Med, AOP Sept. 7, 2018 (#equally contributing first authors; *equally contributing senior authors).

Schlereth K, Weichenhan D, Bauer T, Heumann T, Giannakouri E, Lipka D, Jaeger S, Schlesner M, Aloy P, Eils R, Plass C*, Augustin HG*: The transcriptomic and epigenetic map of vascular quiescence in the continuous lung endothelium. Elife, pii:e34423, 2018 (*equally contributing senior authors).

La Porta S, Roth L, Singhal M, Mogler C, Spegg C, Schieb B, Qu X, Adams RH, Baldwin HS, Savant S, Augustin HG: Endothelial Tie1-mediated angiogenesis and vascular abnormalization promote tumor progression and metastasis. J Clin Invest, 128: 834-845, 2018.

Teichert M, Milde L, Holm A, Stanicek L, Gengenbacher N, Savant S, Ruckdeschel T, Hasanov Z, Srivastava K, Hu J, Hertel S, Bartol A, Schlereth K, Augustin HG: Pericyte-expressed Tie2 controls angiogenesis and vessel maturation. Nature Commun, 8:16106, 2017.

Gengenbacher N, Singhal M, Augustin HG: Preclinical mouse solid tumour models: Status quo, challenges and perspectives. Nature Rev Cancer, 17: 751-765, 2017.

Mogler C, König C, Wieland M, Runge A, Besemfelder E, Komljenovic D, Longerich T, Schirmacher P, Augustin HG: Hepatic stellate cells limit hepatocellular carcinoma progression through the orphan receptor endosialin. EMBO Mol Med, 9: 741-749, 2017.

Augustin HG, Koh GY: Organotypic vasculature: From descriptive heterogeneity to functional pathophysiology. Science, 357, pii: eaal2379, 2017.

Viski C, König C, Kijewska M, Mogler C, Isacke C*, Augustin HG*: Endosialin-expressing pericytes promote metastatic dissemination. Cancer Res, 76: 5313-5325, 2016 (*equally contributing senior authors).

Roth L, Prahst C, Ruckdeschel T, Savant S, Weström S, Fantin A, Riedel M, Héroult M, Ruhrberg C, Augustin HG: Neuropilin-1 mediates vascular permeability independently of vascular endothelial growth factor receptor-2 activation. Science Signal, 9(425):ra42, 2016.

Scholz B, Korn C, Wojtarowicz J, Mogler C, Augustin I, Boutros M, Niehrs C, Augustin HG: Endothelial RSPO3 controls vascular stability and pruning through non-canonical WNT/Ca(2+)/NFAT signaling. Dev Cell, 36: 79-93, 2016.

Savant S, La Porta S, Budnik A, Busch K, Hu J, Tisch N, Korn C, Valls AF, Benest AV, Terhardt D, Qu X, Adams RH, Baldwin HS, Ruiz de Almodóvar C, Rodewald HR, Augustin HG: The orphan receptor Tie1 controls angiogenesis and vascular remodeling by differentially regulating Tie2 in tip and stalk cells. Cell Rep, 12: 1761-1773, 2015.

Mogler C, Wieland M, König C, Hu J, Runge A, Korn C, Besemfelder E, Breitkopf-Heinlein K, Komljenovic D, Dooley S, Schirmacher P, Longerich T, Augustin HG: Hepatic stellate cell-expressed Endosialin balances fibrogenesis and hepatocyte proliferation during liver damage. EMBO Mol Med, 7: 332-338, 2015.

Srivastava K, Ju J, Korn C, Savant S, Teichert M, Kapel SS, Jugold M, Besemfelder E, Thomas M, Pasparakis M, Augustin HG: Postsurgical adjuvant tumor therapy by combining anti-Angiopoietin-2 and metronomic chemotherapy limits metastatic growth. Cancer Cell, 26: 880-895, 2014.

Runge A, Hu J, Wieland M, Bergeest JP, Mogler C, Neumann A, Géraud C, Arnold B, Rohr K, Komljenovic D, Schirmacher P, Goerdt S, Augustin HG: An inducible hepatocellular carcinoma model for preclinical evaluation of antiangiogenic therapy in adult mice. Cancer Res, 74: 4157-4169, 2014.

Hu J, Srivastava K, Wieland M, Runge A, Mogler C, Besemfelder E, Terhardt D, Vogel MJ, Cao L, Korn C, Bartels S, Thomas M, Augustin HG: Endothelial cell-derived Angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat. Science, 343: 416-419, 2014.
Methods that will be used:
Cooperation partners:
Personal qualifications:
The typical PhD student in our laboratory is highly motivated and ambitious, has strong team player skills and is endowed with curiosity and creativity to embark on a challenging high-risk, high-gain project. The group consists in steady-state of 5 postdoctoral fellows and 10 graduate students creating a highly dynamic and interactive working atmosphere. Ideally, PhD students develop their talents through a combination of mentoring and go getter initiative-taking. Incoming students need to have strong hands-on laboratory skills. Experience with mouse work would be a plus, but is not mandatory requirement.
Keywords:
experimental pathobiology, mechanisms of disease, blood vessels, endothelial cells, homeostasis,