MODELING SENESCENCE · Generation of mouse models for the study of cellular senescence in aging and cancer
FP7 — People (Marie Curie Actions)
- Duration
- 2007-12-01 → 2011-11-30
- EU contribution
- €100,000
- Participants
- 1
- Scheme
- MC-IRG
Lines connect the coordinator with its partners.
Results in brief
Generation of mouse models for the study of cellular senescence in aging and cancer
One of the central mechanisms providing protection from cancer in mammals is a cellular programme termed cellular senescence. Senescence is activated by cells in response to various types of physiologic stress, such as deoxyribonucleic acid (DNA) damage, uncapping of telomeres (structures protecting the ends of chromosomes), oxidative stress, and aberrant activation of oncogenes - genes promoting cancer. Senescence is also thought to contribute to organismal aging, and to restrict the renewal of normal stem cells. When cells enter senescence, they cease to divide and undergo a series of dramatic metabolic and morphologic changes. Cellular senescence has been studied for many years in cultured cells, in which the different physiological triggers for it have been characterised, as well as the genes that activate this programme. Studies in recent years have provided strong evidence that cellular senescence does occur also in vivo. It has been shown that senescent cells appear within benign tumours, and it is thought that the activation of senescence at this stage prevents these tumours from progressing to a malignant state. Furthermore, there are indications that stem cells undergo senescence during aging. However, the traits of senescent cells in vivo, their effects on tissue physiology and their subsequent fate are very poorly characterised. To shed light on the nature of this phenomenon in vivo, we have developed mice in which the senescence programme can be activated at will in different tissues. This allows us to characterise the immediate effects of the senescence programme within a physiological tissue context, both in the normal and in the cancerous setting. We found complex and intriguing effects on tissue physiology that are caused by activating the senescence programme in vivo.
Data: CORDIS, © European Union
Project objective
Cellular senescence is a central biological mechanism for cancer prevention in mammals. Cells enter senescence when tumor-inducing genes are aberrantly activated, and in response undergo an arrest in proliferation accompanied by dramatic changes in metabolism and morphology, thus preventing their further development into tumors. Various types of physiologic stresses can also induce senescence, and this process is thought to play a central role in promoting aging, possibly by limiting the proliferative potential of stem-cell pools. While much is known about senescence in cultured cells, basic questions regarding the roles of this process in the living organism are still unanswered. In this proposal we describe the development of systems for the study of senescence in the living organism. We utilize the two central molecular activators of senescence: the p16INK4a and p19ARF genes. These genes are specifically induced during cellular senescence, and their expression is sufficient to induce this state. We will develop and characterize mice in which the expression of p16INK4a or p19ARF can be induced in multiple tissues through tetracycline administration, in order to induce cellular senescence in these tissues. This will allow us to experimentally generate senescent cells in the adult mouse and characterize their molecular and functional traits. We will study the effects of cellular senescence on tissue and organism physiology, and assess whether induction of senescence induces aging-like phenotypes. This system will provide the first genetic system to study this central biological program in its proper physiologic context, shedding light on aging processes and cancer prevention mechanisms.
Original text from CORDIS.
Participants
- THE HEBREW UNIVERSITY OF JERUSALEM · JerusalemCoordinatorIsrael
Links
Data: CORDIS, © European Union