Vascular dysfunction in liver diseases
- Postdoctoral Research Fellow
- Hours of work:
- 37.5 hours per week (excluding lunch hours)
- Annual leave:
- 24 days per annum plus statutory days
- C/ Villarroel 170, 08036 BARCELONA
- Accountable to:
- Professor Manuel Morales-Ruiz
- Up to 3 years, by IDIBAPS
- 38.000 € plus housing facilities
RESEARCH LINE NO LONGER AVAILABLE
1. A postdoctoral position is available in Professor Manuel Morales-Ruiz laboratory. The position involves working wit a team of scientists studying endothelial cell dysfunction in chronic liver diseases and hepatic regeneration.
The programme is a continuation of the work we have published in which we confirmed the presence of important functional changes that affect the hepatic endothelial cells in the context of chronic liver disease. For instance, these cells have a defective activation of the Akt and eNOS enzymes, which is translated into a smaller endothelial vasodilation response (Morales-Ruiz M, et al. Gastroenterology 2003;125:522-531). In turn, the gene expression analysis of the hepatic endothelial cells of cirrhotic livers shows that the majority of the genes differentially expressed are pro-fibrotic, pro-inflammatory and are vasoconstrictors (Tugues S, et al. Gastroenterology 2005;129:1686-1695). In a later study, we analyzed the pathological implications of these transcriptional differences. We treated cirrhotic rats with a multi-target anti-angiogenesis agent, Sunitinib, which inhibits the VEGF receptor specifically expressed in the endothelial cell. The results showed a significant decrease of hepatic angiogenesis, the inflammatory infiltrate and consequently, the hepatic fibrosis. This study demonstrated that the joint inhibition of several pathological processes could be an effective therapeutic strategy in the treatment of cirrhosis (Tugues S et al. Hepatology 2007;46:1919-1926). The validity of this therapeutic approach has been confirmed by other research groups, who have shown that other multi-target anti-angiogenesis agents have the same therapeutic efficiency (reference 9 of the section 2 of this document titled “Introduction”). In turn, the modulation of the pro-inflammatory/pro-angiogenesis phenotype of the endothelial cell has been therapeutically used in other pathologies that deal with chronic inflammation and cancer (Van de Viere S, et al. Cell 2010 141(1): 178-90). On the other hand, recent studies have shown that the endothelial-mesenchymal transition (the process through which the endothelial cells lose their endothelial characteristics and achieve a mesenchymal or myofibroblastic phenotype) contributes to the progression of fibrosis in heart and kidney diseases. It would therefore be reasonable to hypothesize that this phenomenon may also be therapeutically exploited in cirrhosis.
The purpose of this programme of work will be:
- To further the search of anti-angiogenic agents that specifically inhibit pathological angiogenesis. For this purpose, we will evaluate in cirrhotic rats the therapeutic utility and the vascular toxicity of several targets from the VEGF and the angiopoietin signalling pathways
- Investigate molecular, cellular and functional aspects of the mesenchymal endothelial transition (EndMT) in livers from an experimental model of fibrosis in mice. In turn, we will evaluate the therapeutic usefulness of the EnMT blockage by the treatment of fibrotic animals with inhibitors of TGF-beta activity.
- Identify the triggering factors and/or stimuli of the phenotypical transformation of the hepatic endothelial cell (characterized by the synthesis of pro-inflammatory, pro-fibrogenetic and vasoconstrictor molecules). Once identified, we will establish therapeutic strategies to enable the attenuation or reversal of this dysfunctional phenotype. In addition, we will monitor the attenuation of the dysfunctional phenotype of LECs by analyzing the secretome of these cells using high-throughput proteomic technology (SELDI-TOF-MS).
2. The project is likely to involve some or all of the following techniques:
- Molecular biology
- Cell biology
- Experimental models of gene deficiency (knock-out)
To conduct research investigating the role of liver sinusoidal endothelial cells in pathological angiogenesis and liver regeneration
Duties and Responsabilities
- To contribute to the design and planning of experiments in relation to this project
- To develop a thorough understanding of the research field and be involved in the intellectual decision making process required for successful completion of the project
- To set up and run experiments in consultation with the Principal Investigator
- To record, analyse and write up the results of experiments and ensure that laboratory notebooks are kept fully up to date as a formal record of the research
- To prepare and present findings of research to the Principal Investigator and other members of the centre
- To prepare progress reports on research
- The post holder may be required to perform some limited teaching and/or supervision of other members of staff and/or students, under the guidance of the Principal Investigator
- Responsible for ensuring that designated equipment is safe and maintained in good working order
- As duties and responsibilities change, the job description will be reviewed and amended in consultation with the post holder
- The post holder will carry out any other duties that are within the scope, spirit and purpose of the job, as requested by the Principal Investigator
Knowledge and Qualifications
- Undergraduate degree in a life science discipline.
- PhD in an appropriate life science discipline
- Accredited knowledge and skills in molecular biology, gene deficiency experimental models and genomics.
- Proficiency in English language.
- Research stay outside the country of residence.
- Publications in high impact factor peer reviewed journals
- It is expected a thorough background on molecular biology and a clear interest in molecular biology and genomics. In addition, it will be important to show ability to develop ideas logically and design experiments to test hypotheses, ability to modify and apply new methods to advance a project, and to analyse and write up data for presentations and publications
- The post-doc should have a personal resume showing ability to present complex information effectively to a range of audiences and to write effective written and verbal communication skills.
- Ability to direct junior members of the laboratory in simple laboratory procedures
Experience and Personal Qualities
- Experience of working in a research environment and commitment to high quality research
- Experience in multi-disciplinary working and clear interest in working as part of the team. All the members of the team will collaborate in this research project.
- Ability to work independently and to use own initiative when required.