Premature death and organ hypofunction after severe acute pancreatitis results from cellular senescence - mechanisms and new opportunities for therapy

We have discovered that after a serious illness, for example one that needs treatment in intensive care, some people's vital organs do not work as well as they should. This negative effect can last for months and sometimes years afterwards. We have also discovered that people who have suffered a serious illness have a shorter life expectancy compared to others of a similar age, gender and overall general health. This happens even though these individuals appear to have made a complete recovery from their original illness. We believe that this is a serious problem for them and for society as a whole. Our goal is to help people to recover to their full potential after suffering a life-threatening illness.

The idea behind our science is that serious illness results in premature ageing of vital organs within the body, for example the heart and lungs. Our idea is based on discoveries made over many years by us and other scientists. Whenever a cell divides in order for a person to grow or a vital organ to repair itself, for example the cells lining the bowel, liver cells and white blood cells of the immune system, that cell gets a little bit older. After a cell has divided a number of times, or if the DNA inside the cell gets damaged beyond repair, for example during a serious illness, that cell becomes aged. It is likely that these aged cells have stopped working properly. We think that inflammation during a serious illness leads to quicker and earlier aging of cells and that reduces a person's life expectancy.

My area of expertise is looking after patients whose cells have become damaged during a serious illness called acute pancreatitis. Acute pancreatitis is inflammation in the pancreas - a vital organ that controls the digestion of food and blood sugar levels. Our research will be very helpful to people who have had pancreatitis and to those people who look after them. Added to that, we also think that our discoveries will be useful to other scientists and health professionals who study other serious illness, for example severe trauma or major surgery.

Our research will use modern scientific techniques in the laboratory and build on what is already known in the scientific community. We are also going to invite patients who are recovering from pancreatitis to donate blood samples in order to measure damage in their cells, and do some medical tests over a period of time to see how their organs have aged as a result of pancreatitis, and to see how well they recover. When we have a better understanding of how cell damage and cell ageing are linked, we will be able to plan ways to improve a person's recovery after serious illness. We will share our discoveries with the scientific community, and work together to reach our goals.

Even after an apparently complete clinical recovery from an episode of critical illness - for which severe acute pancreatitis (AP) is a paradigm - life expectancy is reduced. In this fellowship, I will investigate the molecular mechanisms that underpin that deleterious legacy, with particular focus on increased flux through kynurenine monooxygenase (KMO) as a key contributor to sterile systemic inflammation and post-inflammatory senescence.
I will define precisely the mechanistic contribution of the kynurenine pathway of tryptophan metabolism, and specifically KMO, on whole-organism and organ-specific accelerated senescence following sterile systemic inflammation using the paradigm model of acute pancreatitis (AP) in human patients and experimental animal models. This coherent portfolio of experiments will dissect the mechanisms by which increased kynurenine pathway flux initiates the DNA damage response (DDR), focusing on oxidative stress generated by the KMO product 3-hydroxykynurenine (3HK), and examining closely the role of the telomere deprotection response (TDR), using models in yeast, primary human lung fibroblasts in vitro, and experimental mouse and rat models of AP. With collaborators, I will develop and validate a novel PET tracer in order to define the organ-specific KMO activity profile during experimental AP and allow correlation with organ-specific post-inflammatory senescence at subsequent time points. Biological indices of the DDR, TDR, the senescence-associated secretory phenotype, cellular and whole-organism senescence will be examined in models and contextualized to chronic organ hypofunction in a clinical cohort as a legacy of human AP and AP-MODS.

This project deals with the effect of severe whole-body inflammation on premature cellular ageing, and how individuals recover after critical illness to a state that allows them to return to a healthy and productive life. Therefore, this research is of importance to multiple sections of society, including individuals who have suffered an episode of critical illness, families and loved ones, local communities, healthcare organizations, policy makers and healthcare providers. We will strive for excellence with impact, and maximize the economic and societal benefits of this research. By understanding the deleterious legacy of critical illness, over time we will be able to improve recovery and prevent lasting organ damage. We envisage that this will increase the likelihood of individuals at working age returning to their chosen work, with the economic benefits that that will bring, individually and to society, decrease the burden on health resources and increase happiness through increased physical and mental well being. In an ageing population, understanding the molecular processes that contribute to the ageing process, especially after an episode of critical illness will undoubtedly increase in importance. I am focusing on acute pancreatitis (AP), which affects 30,000 individuals in the UK every year, but we expect that the underlying molecular mechanisms that we will define will be translatable to other situations of systemic inflammation, for example trauma and major surgery. Because of the overlap between the DNA damage response, ageing and cancer, there is a high likelihood that our work will also shed light on how cancer can develop after long-standing inflammation. Importantly, in the execution of our project, we will be mindful of the different potential pathways of realizing impacts, such that the funding invested in the project by the MRC is used to its maximum potential. Life sciences research is integral to society and the UK economy, and the UK has always punched above its weight in this sector. Having maximum impact and using that economic potential to the full is one of our uppermost priorities. It is through these vehicles that we can use our research skills, our communication and networking skills to encourage inward investment to UK Life Sciences research and boost the economy. The short-term economic benefits of our research are important, in terms of encouraging inward investment to the UK and collaborating with important players in UK plc., for example our interdisciplinary DPAc with GSK. In the longer term, we will maximize knowledge exchange and translation to generate the widest range of economic and societal benefits through this internationally competitive research project. This research project has the potential to give significant insight into the healing process and preventing lasting organ damage; this knowledge will enable innovations that speed-up recovery and guide individuals back to a better state of health after critical illness. Translation of these interventions may be complex - developing new medicines (for which we have experience); of medium complexity - repurposing existing medicines; or straightforward in concept (if not necessarily execution) - for example dietary or lifestyle interventions, or increased awareness of problems that individuals might expect to experience. I am fortunate to be in regular contact with Third Sector organizations, in particular Core (a charity that funds research, public engagement, patient information, focusing on gastrointestinal disease and pancreatitis) and The Health Foundation, an influential independent charity that engages in policy and healthcare development in strategic ways. I will use those networks, and all my other networks, especially my peer group and professional community to maximize our impact. I hope to join with others in our shared commitment to promote a dynamic and internationally competitive research and innovation base in the UK.