Project: towards understanding and treatment of paraganglioma’s.
Pheochromocytomas and paragangliomas (PGLs) are rare tumors of parasympathetic and sympathetic paraganglia. Besides being tumors, sympathetic PGLs secrete excess catecholamines, giving severe headache, panic attacks, arrhythmias and hypertension. Germline mutations in 12 genes confer susceptibility for PGL development in 25-40% of sporadic tumors, which fall into two clusters leading to hypoxia-inducible factor-1/2α(HIF-1/2α)-dependent tumorigenesis. Cluster 1 genes involve inactivating mutations in proteins of the Krebs cycle, such as succinate dehydrogenase(SDH) subunits A-D. Most metastatic PGLs are associated with germline mutations in SDHB and predispose to malignancy in 37-97% of the cases. Treatment for SDHB PGLs, however, is lacking and thus appropriate model systems and specific therapeutic targets for these tumors are urgently needed.
The goal of the present project is to set up a proper adrenal cell for SDHB PGLs using CRISPR technology and to use these models to study the aetiology of the disease in vitro and in vivo, and to screen/test potential therapeutics. Moreover, we will set up a cellular system to screen for inhibitors of a potential therapeutic target and test the effect of its blockers on the SDHB phenotype in our cell/fish models.
The project is part of the international ‘paradifference’ consortium and is a collaborative project of the dept of internal medicine and Physiology. The dept of internal medicine has a long-standing tradition to molecularly analyse and treat PGL patients, whereas the department of Physiology has a strong expertise in molecular, cellular and animal pathophysiology. In this project, the applicant will work within the dept. Physiology, which is, together with basic science and research-oriented clinical departments of the Radboud University Medical Center, housed in the "Radboud Institute for Molecular Life Sciences (RIMLS, www.rimls.eu)", which integrates diverse scientific expertise in molecular and medical science for the advancement and innovation in translational research.
The ideal candidate has:
- A MSc in molecular/cellular physiology/endocrinology or related field.
- A permit to work with animals (art. 9).
- Preferentially experience in using CRISPR technology and/or metabolic flux analysis.
- Structured working style
- Good English writing and presentation skills
- A strong motivation, flexibility, and willingness to learn
- The ability to work and interact with others in an energetic and supportive research group
Major research responsibilities for this position:
- Generation and maintenance of SDHB-mutated adrenal cell line.
- Biochemical analysis for the PGL phenotype in cells.
- Setting up a cellular screening system for the potential therapeutic target
- Data analysis and interpretation.
- Contribution towards preparation and submission of manuscripts.
- Presentation of data and communication with research partners
The position is open until filled.
What we offer:
- Exciting and innovative project
- Stimulating and productive scientific environment in an international setting.
- Salary and contract is based on research experience and qualifications.
Further information and contact
Salary is according to CAO-RUNMC. Additional information about the vacancy can be obtained from Prof. Peter MT Deen/Dr. H. Timmers (peter.deen or email@example.com). Detailed information about the departments and affiliated network centres can also be found at www.physiomics.eu, www.radboudumc.nl (search terms: Internal Medicine and Radboud Adrenal Centre) and www.ensat.org. Applicants should send a letter of intent outlining special interest in the position, overall related qualifications, experience and career goals, a curriculum vitae and names and addresses of professional references to us via firstname.lastname@example.org.
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