Ageing is a process defined by the accumulation of old (senescent) cells in tissues. It has been shown that senescent cells interfere with the normal functions of tissues and thus lead to the phenotypic changes associated with ageing as well as the establishment of age-related diseases. Together, these are responsible for loss in quality of life and the eventual reduction of lifespan of an organism. The genetic factors involved in triggering and maintaining senescence have not been fully characterized. Our main goal is to take advantage of novel markers and effectors of senescence, particularly those related to the p53 pathway, in order to:
1. better understand the molecular processes involved in human ageing.
2. define new therapies that target senescence, which should:
- ameliorate age-related diseases, such as cancer, fibrosis and neurodegenerative diseases.
- delay and/or ameliorate the symptoms of ageing, with the final goal of slowing/reverting the process in humans.
Through an initial proteomics screening, we identified several novel potential components of the senescent pathway[1], and we showed that inhibition of one of them delays ageing in a mouse model[2] due to its control of p53[3]. We propose to study the role of these proteins in senescence and ageing. Our research plan will include:
1. Assessing the effects of potential effectors of senescence by inhibiting/overexpressing them in different cellular models (such as fibroblasts aged in culture or derived from premature ageing syndromes, or stress-induced senescent normal and cancer cells). By doing this, we will also study the changes in gene expression that define the senescent phenotype. Preliminary data suggests that certain chemical inhibitors of these proteins can block senescence. We will test their effect on cell ageing.
2. Defining novel markers of senescence. The methods currently available to detect senescent cells need to be improved. We plan to characterize several novel membrane proteins upregulated in senescence to be used as new and more efficient markers. We have recently shown that such markers could have prognostic potential in diseases such as cancer. With the help of our collaborators, we will develop systems to detect senescent cells in tissues and in culture. This has therapeutic potential (see below) but could also be useful to determine the percentage of senescent cells in tissues and thus its biological ageing. Comparisons to chronological ageing could have diagnostic and prognostic value.
3. Establishing new protocols for clearing senescence cells. It has been shown in mouse models that eliminating senescent cells from tissues suppresses the symptoms of ageing and prolongs lifespan[4]. We will use our newly identified markers to selectively target senescent cells using nanotechnology, monoclonal antibodies, etc. This aim will also be performed with our collaborators at the Department of Chemistry and commercial partners, which will provide targeted compounds that could selectively detect and kill senescent cells. We will also test them in in vivo models if possible.
We expect our experiments to clarify the mechanisms involved in the senescence pathway, which are still poorly defined, as well as to provide new tools for the study of senescent cells and possible diagnostic/therapeutic interventions that could increase health and quality of life in older populations in the future.
Entry requirements:
• Those who have a 1st or a 2.1 undergraduate degree in a relevant field are eligible.
• Evidence of quantitative training is required. For example, AS or A level Maths, IB Standard or Higher Maths, or university level maths/statistics course.
• Those who have a 2.2 and an additional Masters degree in a relevant field may be eligible.
• Those who have a 2.2 and at least three years post-graduate experience in a relevant field may be eligible.
• Those with degrees abroad (perhaps as well as postgraduate experience) may be eligible if their qualifications are deemed equivalent to any of the above
• University English language requirements apply. https://le.ac.uk/study/research-degrees/entry-reqs/eng-lang-reqs/ielts-65
For further information please contact [Email Address Removed]
Application advice:
To apply please refer the application instructions at https://le.ac.uk/study/research-degrees/funded-opportunities/bbsrc-mibtp
You will need to apply for the PhD place and also submit your online application notification to MIBTP. Links for both are on the above web page.
Project / Funding Enquiries: For further information please contact [Email Address Removed]
Application enquiries to [Email Address Removed]
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