Deciphering the tissue-specific role of the transcription factor SKN-1B in C. elegans to promote a long and healthy life.

Lead Research Organisation: University of Kent
Department Name: Sch of Biosciences

Abstract

With age, it is unfortunate that humans succumb to a variety of debilitating conditions e.g. brain degeneration, diabetes, heart problems and muscle degeneration to name but four. However, it is difficult to study ageing in humans due to the time scales involved. To circumvent this problem, scientists use simpler organisms such as worms, flies and mice. In particular, studies with a nematode worm (Latin name C. elegans) have been instrumental to discovering and understanding the ageing process. For example, it is possible to increase or decrease lifespan in worms by altering the activity of various molecules and amazingly, interventions that extend lifespan often also improve the age-related health of the animals. Thus, these studies have shown that it is possible not only to extend lifespan but also the quality of life. As most of the molecules identified in this research are also present in human cells, by studying their effects on lifespan in simple organisms, we will eventually be able to use this information to design approaches to slow ageing and improve the late-life health of humans.

In worms, one important ageing molecule is called SKN-1. It is equivalent (in terms of its function) to the human Nrf proteins. If SKN-1 activity is decreased then worms have a shorter lifespan and, conversely if SKN-1 activity is increased so is their lifespan. Understanding how SKN-1 works is therefore key to understanding the ageing process and developing ways to intervene in it. SKN-1/Nrf has a very important role in cells because it allows them to respond to and survive stressful conditions. It is also very important for regulating protein homeostasis and metabolism. We want to understand how these and other functions are important for controlling ageing and as the SKN-1 molecules present in worms are similar to those in humans, our work has real relevance to a better understanding of human ageing.

There is currently considerable interest in identifying genetic or chemical modulators to extend lifespan and thus improve lifelong health. We know that SKN-1 is important for these processes and, it is particularly interesting to study as it is already an established drug target. So, by defining how it works we will be able to harness this to develop anti-ageing therapies and therefore lay the foundations of knowledge that will be useful for promoting long and healthy human lives.

Technical Summary

Ageing is correlated with many of the debilitating conditions suffered by humans later in life. By studying the molecules that control ageing we will be able to design interventions that slow it down and improve late-life health. In C. elegans, extending lifespan either by reducing insulin signaling (e.g. daf-2 mutation) or by dietary restriction requires the key transcription factor SKN-1. The importance of SKN-1 for lifespan is also supported by the fact that knockdown of SKN-1 expression or increasing its activity (by increasing levels or chemical activation) decreases or increases the lifespan of wild type C. elegans, respectively. Our overall aim is to identify the function and molecular basis of SKN-1 since this will be key to understanding the ageing process and developing ways to intervene in it.

Many processes and pathways in worms also exist in mammals, and the worm has proved invaluable for identifying these and illustrating their potential. SKN-1 is an important stress response protein and allows the cell to protect itself against a variety of environmental onslaughts as well as regulating lifespan. As SKN-1 is well conserved (mammalian Nrf counterpart), and is a 'drugable' molecule, this work will provide critical information for studies aimed at identifying novel anti-aging therapies. Worms have multiple isoforms of SKN-1, each with distinct functions, and it is likely that the combined functions of these isoforms represent the role of its mammalian counterpart Nrf. Our preliminary experiments have unearthed novel functions of one of these isoforms, namely SKN-1B, in regulating both lifespan and age-related health. This project will fully characterise SKN-1B, defining its functional role in ageing and its regulation. This work is critical to our full understanding of the molecular detail underlying SKN-1/Nrf function so that we can fully exploit worms as a model for mammalian ageing processes.

Planned Impact

Effectively disseminate the results throughout the scientific community.
The research proposed is of a basic nature and the immediate impact of the work will be on the bioscience research community with an interest in ageing. As SKN-1 is conserved any novel findings we make in C. elegans are also of interest to the mammalian Nrf field. Longer term, the public will also benefit as this research has potential to impact on human healthcare and possibly anti-ageing therapies. The findings of this project will be published in high quality, peer reviewed journals and presented at national/ international conferences. Where appropriate, we will publish press releases via the University press office and our website (below), targeting local and national media.

Protect our discoveries and to promote our findings to suitable industries.
There is intense interest from scientists, the public and the pharmaceutical industry (medical and cosmetic sectors) in molecules that affect ageing. Major discoveries resulting from this work will be protected via the University of Kent's Innovation and Enterprise (KIE) Office. This will be co-ordinated by Dr Gary Robinson who is (uniquely) senior lecturer in Biosciences and KIE's senior commercialisation manager. This will allow us to evaluate, exploit and protect our results from this project. There is also a University industry liaison officer, who can communicate our latest research and encourage industrial partners to participate in their exploitation.
Train the PDRA to a high standard and equip them with the skill set necessary to succeed in their future, independent career. There is provision for skills training from the University and a Biosciences post doc group co-ordinated by the PI. The PI recognizes that the development and success of the PDRA will directly influence the outcome of the project and is committed to making it a productive relationship.

Communicate our findings to the general public.
Most people relate to and are interested in the topic of ageing thus, it is important that our research is communicated clearly to the public. The applicant has previous experience in dealing with the public (Royal Society and Science Museum exhibits), the press (BBC world, The Guardian), and online communication (TED style talks, "I'm a scientist get me out of here" and "naked genetics" podcasts). As a lab, we will fully participate in Kent's School of Biosciences' outreach program. In particular the dissecting microscope camera and PC requested for this project will be of use for outreach work (e.g. taking the setup into schools to show the students live worms and explain our research) as they allow us to demonstrate worm manipulation to larger groups. This outreach work also includes the MBP2 project at Simon Langton Grammar School (Canterbury) as well as a stream of invited talks at other schools in the area.
To further promote our work we will develop a lab website on which our research activity will be recorded. We request funds for this so that a summer student can get the site established. This website can then be used to advertise our lab to future potential lab members, the scientific community and the general public. Kent's website will also carry information on the project, summarising results and publications for scientific and lay audiences.

Overall management of impact.
The PI will drive this impact scheme, but will discuss further collaborations or partnerships with the collaborators. There is significant support and advice for the management of this plan provided by well-established links with the University, by Kent Innovation and Enterprise and the Kent Outreach Partnership Development Office. In summary, this project has an ambitious, but achievable, plan for impact at local, national and international levels.

Publications

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