Identification Of New Mediators Of Cellular Senescence, And Their Role In Development, Cancer And Regeneration.
Reference : PhD Bill Keyes
Offer publication : April 28, 2016
Cellular senescence is an important cellular process that restricts tumor growth at the cell-intrinsic level, but which can promote growth through the senescence associated secretory phenotype (SASP), the secretion of a wide variety of proteins by senescent cells (Keyes et al, Cell Stem Cell, 2011). Senescence is also a key driver of aging, through cell intrinsic effects from the accumulation of senescent cells, as well as an accumulated
SASP having detrimental effects on tissue function (Doles et al, Genes Dev., 2012).
Recently, we identified that senescence is also a programmed
process during normal embryonic development, the first time senescence has been seen in a non-pathological state in vivo (Storer et al, Cell, 2013). We identified senescent cells in major signaling centers including the hindbrain roof plate of the neural tube and in the apical ectodermal ridge of the developing limb, where senescent cells are thought to play roles in cell fate instruction, tissue patterning and remodeling. Furthermore, in unpublished work, we have found how cells undergoing oncogene-induced senescence, through the SASP, can promote stem cell fate and tissue regeneration, and which is likely mediated through conserved, yet unknown pathways shared with developmental senescence. Therefore, the identification of non-pathological senescence in the embryo offers a significant opportunity to better understand the important process of
We aim to identify new mediators of the senescence program, and to investigate their functional contribution to the senescent
state. To achieve this, we will perform molecular profiling of senescent cells purified from the embryo, and of cells undergoing oncogene-induced senescence, and investigate those genes whose expression is increased in both states.
The objective of the project is to functionally investigate these new genes in regulating the process of cellular senescence. This will involve manipulation of these genes through knockdown and overexpression in different cellular models of senescence, including oncogene- and irradiation-induced states. The effects on senescence establishment will then be measured using a variety of cell-based, genetic and epigenetic assays. In addition, the expression and functional role of these genes will also be analyzed in animal models of senescence, including during normal embryonic development, in premalignant lesions, and in tumors. We predict these genes will play important roles in normal embryonic development, stem cell-fate specification, tissue regeneration or cancer.
WISHED SKILLS :
- A high motivation to perform basic science research, and a willingness to work hard to achieve results.
- A strong interest in senescence, stem cells, tumor initiation or normal embryonic development.
- To be able to work as part of a team, as well as independently.
- Fluency in English is required.
- Preliminary experience in any aspect of general cell biology, genetics or with animal models.
EXPERTISES WHICH WILL BE ACQUIRED DURING THE TRAINING :
How to perform scientific research, and to develop a project. Attending and preparing scientific presentations, analysis and interpretation of scientific literature,writing of publications.
Scientific skills can include; tissue culture; retroviral over-expression ; shRNA generation and use; immunolabeling; cell-based assays (senescence, apoptosis, proliferation, invasion); FACS analysis; genomic and transcriptomic analysis (RNA-sequencing, ChIP-sequencing); in vivo analysis using
mouse models, (development, tumors); immunohistochemistry, in situ hybridization, microscopy
Application Deadline : Dec. 31, 2016