Α variety of major diseases, such as Alzheimer's disease, Huntington's disease, systemic amyloidosis, cystic fibrosis, type 2 diabetes etc., are characterized by a common molecular origin: the misfolding of specific proteins. These disorders have been termed protein misfolding diseases and the vast majority of them remain incurable. The goal of the ProMiDis project is to develop an efficient technology for early drug discovery against these conditions, which will be generally applicable to various protein misfolding diseases. This includes diseases caused by the misfolding of both soluble and integral membrane proteins.
In the framework of the ProMiDis project, we will generate engineered bacterial cells that function as a broadly applicable discovery platform for compounds that rescue the problematic folding of misfolding-prone and disease- associated proteins (MisPs). These compounds will be selected from libraries of drug-like molecules biosynthesized in engineered bacteria using a technology that allows the facile production of billions of different test molecules. These libraries will then be screened in the same bacterial cells that produce them and the rare molecules that rescue MisP misfolding effectively will be selected using an ultrahigh-throughput genetic screen. The effect of the selected compounds on MisP folding will then be evaluated in detail by biochemical and biophysical methods of protein analysis, while their ability to inhibit MisP-induced pathogenicity will be tested in appropriate mammalian cell assays and in established animal models of the associated PMD in the nematode C. elegans. The molecules that rescue the misfolding of the target MisPs and antagonize their associated pathogenicity both in vitro and in vivo, will become drug candidates against the corresponding diseases. This procedure will be applied for different MisPs to identify potential therapeutics for four major PMDs: (i) Huntington's disease; (ii) cardiotoxic light chain amyloidosis; (iii) dialysis-related amyloidosis; and (iv) retinitis pigmentosa. ProMiDis will deliver invaluable therapeutic leads against major diseases and a unified framework for anti-PMD drug discovery.
The Biomedical Sciences Research Center “Alexander Fleming” (BSRC FLEMING) (www. fleming.gr/) is the top-ranked Greek non-profit research organization focusing on scientific and technological excellence, innovation and training in the Biomedical Sciences. Currently, it consists of two individual research institutes:
The Institute of Fundamental Biomedical Research (IFBR), which focuses on unraveling the molecular and cellular basis of diseases, identifying new molecular targets for therapeutic intervention, developing new animal models for mimicking human diseases and establishing new state-of-the-art technologies in biomedical sciences - and
The Institute of Bio-Innovation (IBI), whose mission is to advance basic research discoveries towards innovation in the areas of biotechnology, drug discovery and development. IBI aspires to fill the gap between basic and applied research by promoting the translational potential of the basic biomedical research discoveries generated by BSRC FLEMING researchers and combining it with more applied biotechnological/biomedical expertise of other BSRC FLEMING groups, to deliver innovative health-promoting products of high- added value and socio-economic benefit.Required Research Experiences
Biological sciences › Biological engineering
4 - 10
Chemistry › Biochemistry
4 - 10Offer Requirements
Biological sciences: PhD or equivalent
Chemistry: PhD or equivalent
Engineering: PhD or equivalent
Candidates should have a PhD in biochemical engineering, biotechnology, molecular biology, biochemistry, pharmaceutical sciences or related disciplines. They should also have a strong publication record.
The successful candidate is expected to have a strong drive to pursue research, be organized and structured and have an ambitious and innovative attitude. The successful candidate is also expected to have service awareness and high interpersonal communication skills, ability to work independently, as well as responsibility, initiative and self-learning abilities. The project is highly inter-disciplinary and pursued in collaboration with other research groups, and good collaborative skills are necessary.
Desired technical skills: studies of protein folding, misfolding and aggregation in the test tube, in microbial or mammalian cells and/or in laboratory animals; recombinant DNA technology; protein engineering; directed protein/peptide evolution; high-throughput genetic selection and screening; flow cytometry and fluorescence-activated cell sorting (FACS); protein purification (soluble or integral membrane proteins); protein biochemistry (soluble or integral membrane proteins), protein biophysics (soluble or integral membrane proteins). Candidates should have excellent knowledge of the English language.Contact Information