Structural Dynamics Of The Nuclear Receptor Ppar-Gamma: Implications In The Carcinogenesis Of Bladder Tumors
Reference : PhD STOTE Roland
Offer publication : April 5, 2016
Nuclear receptors (NR) are the largest family of transcription factors that regulate the transcription of genes in metazoans. They control many processes related to cell cycle, differentiation, apoptosis, development, reproduction and homeostasis. An important feature of NRs is that their regulation of gene expression is dependent on the fixation of small ligands. The NR family includes steroid hormone, thyroid hormone, vitamin D and
retinoid receptors, as well as receptors that bind lipid metabolism regulators. The ligand dependent activity of NRs makes them central targets for drug development in many diseases such as diabetes, arteriosclerosis, inflammatory diseases, cancer, etc.
Genetic alterations of members of the nuclear receptor family, Peroxisome proliferator-activated receptor gamma (PPARg) and the retinoid X nuclear receptors (RXR) have been identified and associated to a particular subgroup of muscle invasive luminal bladder tumors. This, coupled with other data, suggests a protumorigenic activity of the PPARG-RXRA complex when activated by different mutations in these luminal tumers.
These data underscore the need for increased study of the role of PPARgin the development of bladder cancers and calls attention to the necessity to better understand the molecular mechanism of action and the effects of PPAR-specific mutations linked to bladder cancer progression.
The aim of the PhD project is to investigate the structure-dynamic-function relationship and molecular mechanisms of interaction and to characterize the changes in structural dynamics induced by the PPARg and RXRa mutations, their binding to DNA and to co-activator proteins and to identify
ligands that may modulate the structure/activity. We will concentrate on several activating mutations that target different PPARg domains. We will use methods in computational biophysics to evaluate their impact. We expect that this project will have an impact by improving our understanding of PPAR
ligands, which could contribute to improving anti-cancer treatments by facilitating the development of molecules that might be used alone or in combination with other agents to modulate the PPAR action in pathological situations.
The work will require the development and implementation of effective methods of molecular simulations to study allosteric effects on the functional dynamics of the NRs.
The project is developed in collaboration with teams in experimental biophysics and cellular molecular biology.
- WISHED SKILLS : This project is aimed at biologists/bioinformaticians, computer scientists, chemists or physicists with a strong motivation for developing innovative methods in molecular modeling and apply them to biologically relevant problems. A working knowledge of the UNIX/Linux
operating system, and programming skills are necessary, as well as basic knowledge in structural biology (protein structure and principle of macromolecular recognition).
- EXPERTISES WHICH WILL BE ACQUIRED DURING THE TRAINING : The thesis student will develop his scientific culture at the biology-chemistry-physics interface and will reinforce his/her practical training in computers and programming, as well as in cutting-edge methods for numerical simulation and molecular modeling. This background will open opportunities for industrial (mainly pharmaceutical or software companies) as
well as academic careers.
Application Deadline : Dec. 31, 2016