Ruprecht-Karls-Universität Heidelberg
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Ola0120 - Scientist (f/m) / PhD position
Project no:
Ola0120

Project leader:

Project supervisor:
Ola, Roxana
Application deadline:
29. Feb 2020
Start of PhD project:
1. Apr 2020

Project description:

Title:
TGF-Beta/BMP signalling in cardiovascular homeostasis and disease
Summary:
Mutations or dysregulation of TGF-β/BMP signaling pathway leads to vascular dysfunction in multiple vascular disorders including arterio-venous malformations (AVM), a clinical manifestation of Human Hereditary Hemorrhagic Telangiectasia (HHT) vascular disorder.

We recently discovered that in murine models of HHT, AVM formation is potentiated by increased blood flow and it is exclusively a pathogenic feature of BMP9 and BMP10 signaling through Activin like kinase 1 (ALK1) and Endoglin (ENG) receptors, and that SMAD4 acts as an essential effector in AVM pathogenesis (Ola et al., 2016; Lee, Chong, Ola et al., 2018; Ola et al., 2018).

My lab is looking for a PhD candidate that will study the cellular and molecular mechanisms responsible for AVM formation in mouse models of HHT. He/She will focus mainly on the crosstalk between blood flow and SMAD4 signaling in maintaining blood vessels quiescence and stability. In collaboration with Prof. Dr. Nima Etminan, the head of neurosurgery clinic we would like to translate our bench results to the human pathology.
References:
Ola Roxana, Künzel SH, Zhang F, Genet G, Chakraborty R, Fragner LP, Martin K, Sessa W, Dubrac A, Eichmann A. SMAD4 prevents flow induced arterial-venous malformations by inhibiting Casein Kinase 2. Circulation. 2018; 138:2379-2394.

Ola Roxana, Dubrac A, Han J, Fang JS, Zhang F, Larrivée B, Lee M, Urarte AA, Kraehling JR, Genet G, Hirschi KK, Sessa WC, Canals V, Graupera M, Yan M, Young LH, Oh SP, Eichmann A. PI3 Kinase inhibition improves vascular malformations in mouse models of Hereditary Hemorrhagic Telangiectasia. Nat. Commun. 2016; 7, 13650.

Lee HW,* Chong D,*, Ola Roxana,* Dunworth WP, Meadows S, Ka J, Kaartinen V, Qyang Y, Cleaver O, Bautch V, Eichmann A, Jin SW. Distinct requirement of Alk2/ACVR1 and Alk3/BMPR1A in bone morphogenetic protein induced retinal angiogenesis. Arterioscler Thromb Vasc Biol. 2017; 37:657-663.

Baeyens N,* Larrivée B,* Ola Roxana, Hayward B, Dubrac A, Huang B, Ross TD, Coon B, Tsarfati M, Tong H, Eichmann A, Schwartz MA. Defective fluid shear stress mechano transduction mediates hereditary hemorrhagic telangiectasia (HHT). J Cell Biol. 2016; 214:807-16.
Methods that will be used:
conditional knockout mice, FACS sorting, PCR genotyping, primary cell cultures, IHC, Western Blot, RT-PCT, RNA sequencing, transcriptomics, proteomics
Cooperation partners:
Prof. Hellmut Augustin, Prof. Dobreva Gergana, Heidelberg University, Germany
Prof. Christer Betsholtz, Uppsala University, Uppsala, Sweden
Prof. Elisabetha Dejana, in vascular stability, IFOM, Milano, Italy
Dr. Alexandre Dubrac, Department of Pathology and Cellular Biology, Université de Montréal, Canada
Prof. Anne Eichmann, Cardiovascular Research Center, Yale University, New Haven, USA
Prof. Anna Randi, Imperial College London, UK
Prof. Martin Schwartz, Cardiovascular Research Center, Yale University, New Haven, USA
Personal qualifications:
We are looking for a highly motivated PhD student with a background in molecular and cell biology. A strong interest in vascular biology and bioinformatics analysis would be a plus. You will become a member of the ECAS (European Center of AngioScience) at Faculty of Medicine, Heidelberg University. ECAS comprises 7 other laboratories in Heidelberg University with a broad interest in cardiovascular research. You will participate in activities within the ECAS consortium with the collaboration partner at DZHK and the University Clinics. All this will provide you with the opportunity to acquire expertise in cutting-edge cell, molecular cell and translational vascular research.
Keywords:
angiogenesis, vascular malformations, BMP signalling pathway, cardiovascular disorders