Award details

Talking to the Clock: Understanding How The Molecular Circadian Clock Is Regulated By The Cellular Environment

Reference	BB/N01992X/1
Principal Investigator / Supervisor	Dr Aarti Jagannath
Co-Investigators / Co-Supervisors
Institution	University of Oxford
Department	Clinical Neurosciences
Funding type	Research
Value (£)	1,011,606
Status	Current
Type	Fellowships
Start date	01/04/2017
End date	30/09/2023
Duration	78 months

Abstract

The molecular circadian clock is expressed in most cells of the body and governs daily rhythms in physiology and behaviour, including the sleep-wake cycle. Whilst there have been great advances in our understanding of the core clock machinery, we know very little about how it is set to the right time. In order for the circadian network to have adaptive value, it must receive and respond to signals from the environment that provide temporal cues. These include light, but also numerous other signals such as food and hormones. The aim of my proposal is to investigate the molecular mechanisms that underlie the communication between the external and intracellular environment and the clock itself. This will be done at three levels: 1) Characterise signaling pathways that relay information from the extracellular space to the clock. 2) Identify genes that can modulate the response of the molecular clock. 3) Outline post-transcriptional regulation of the molecular clock by microRNAs. The circadian clock is central to health and wellbeing and its importance as a target for chronic and hard-to-treat disorders such as diabetes is becoming increasing recognized. Uncovering the molecular mechanisms by which the clock can be modulated would reveal in turn definitive routes to the development of chronotherapeutic strategies.

Summary

All organisms display daily rhythms in physiology and behaviour, such as the sleep-wake cycle, but also including rhythms in blood pressure, body temperature and cognitive ability. These rhythms are driven by a circadian (circa-around, diem-day) clock that is a molecular pacemaker occurring in most cells throughout the body. In order for this clock to serve its purpose, it must be synchronized to external environmental cues, such as the timing of the day-night cycle and availability of food. Our understanding of how this clock is set to the correct time is very basic. I propose to use cellular models of the clock to understand how external factors both within and external to the cellular environment relay information to the molecular clock and how this information is integrated. We are now realising that disrupted circadian rhythms can lead to a wide range of conditions that impact quality of life and healthy ageing, such as diabetes and mental illness and that the circadian clock represents a novel and untapped target for these conditions. My research will provide new avenues by which the clock can be targeted for therapeutic purposes. This work will be undertaken at the Sleep and Circadian Neuroscience Institute at the University of Oxford in collaboration with the Departments of Pharmacology at Oxford, the University of Geneva, F. Hoffman-La Roche, Basel and Axolabs GmBH, Germany.

Impact Summary

The main deliverables are 1) a mechanistic understanding of the pathways by which environmental signals are relayed to the molecular clock (these will provide the substrate with which to develop interventions targeting the circadian network) and 2) the identification of specific genes, miRNAs and safe and approved drugs that could provide the basis for these interventions. These findings will increase our understanding of the regulatory networks underlying biological rhythms, and provide tangible outputs that will find application in disease areas where circadian disruption is implicated. These include obesity, diabetes, cardiovascular disease, mental health disorders and cancer, which together cover the top 3 spending areas of the NHS and cost the economy over £100 billion. These disorders are also the major factors underlying a substantially shorter healthspan in comparison to lifespan. This findings from this research will directly benefit 1) Academic labs researching disease mechanisms in the above areas. This work will provide an advanced understanding of mechanisms underlying clock regulation, chronomodulatory tools and biological databases of broad interest. 2) Pharmaceutical industries working on metabolic disease, oncology and mental health disorders. The findings from this project will inform and shape their drug-discovery strategies and contribute to the health and competitiveness of the industry. The collaboration with F.Hoffman-La Roche indicates their interest in this work, and opportunities for further development of the findings will be discussed. 3) University-led drug discovery programs focusing on similar areas as above, especially those groups interested in developing novel treatments for mental health (an area receiving little investment from the pharmaceutical industry in recent times). The findings will especially benefit reprofiling efforts, or finding new uses for existing safe, and off-patent drugs. Via these groups, which include Oxford'sDepartment of Pharmacology, the findings from my project could be translated to the benefit both science and society. My collaborators Dr. Vasudevan and colleagues have significant success in this area, having developed a lithium mimetic drug that was translated from the bench to clinical application in under four years. 4) Biotech companies, specifically RNAi companies such as Axolabs, Alnylam and Regulus Therapeutics, which develop RNAi and miRNA based therapeutics for diseases including cancer. The collaboration with Axolabs GmbH indicates their interest in this work, and opportunities for further development will be discussed. 5) The healthcare sector, as these findings can underpin the development of new therapeutics to treat chronic and debilitating conditions as discussed above. The findings will also result in an increased understanding of adverse effects of widely used drugs and also how clocks in different tissues can be affected by disease. This information will provide valuable guidance for supporting patient and aging populations. 6) Policy makers and bodies that disseminate information to the wider public including charities and the media. Policy makers will benefit from a better understanding of environmental factors that can shift circadian rhythms, which may lead to better guidelines on working practices and recommendations for healthy ageing. This information will be disseminated by the dedicated outreach wing of the SCNi via workshops, roadshows, television and press releases, etc. In terms of staff development, I will gain additional skills in research, personnel management, and a platform to develop as a PI. The post-doctoral research assistant on this program will gain research skills and technical expertise, applicable in the wider field of cell and molecular biology research. In addition, they will gain writing, presentation and project management skills, which would be of benefit in all employment sectors.

Committee	Research Committee D (Molecules, cells and industrial biotechnology)
Research Topics	Neuroscience and Behaviour
Research Priority	X – Research Priority information not available
Research Initiative	Fellowship - David Phillips Fellowship (DF) [1995-2015]
Funding Scheme	X – not Funded via a specific Funding Scheme

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