The Signalling & Cell Fate ISP

The normal development and lifelong health of an organism, including man, is dependent on the coordinate control of cell fate decisions including: whether to proliferate and divide; undergo cell cycle arrest and differentiate; permanently withdraw from cell cycle and senesce and survive or die.  These cell fate decisions are controlled by extrinsic signals including growth factors, hormones and environmetnal stressors and intrinsic signals such as the accumulation of oxidative damage to DNA, proteins and lipids throughout a normal lifespan.

The capacity of cells and tissues to respond to damage and environmental signals varies considerably.  For example, self-renewing stem cells are endowed with the ability to replace damaged/dead cells to maintain tissue function and health throughout life.  However, defects that undermine self-renewal can lead to impaired tissue regeneration, a characteristic of old age.  It is therefore critically important to understand how decisions to divide, differentiate, senesce or die in response to environmental challenges are controlled.  In contrast, terminally differentiated cells (e.g. neurons) encounter similar environmental challenges but have little or no capacity for cell replacement; they must adapt to stress to survive and maintain tissue function.  Failure to do so leads to attrition of functional differentiated cells in the adult and a progressive increase in frailty in the ageing population.  When cells do die, programmed cell death must remove them in a controlled manner to avoid damage to neighbouring tissues.

Extrinsic and intrinsic signals are interpreted within the cell by activation of signal transduction cascades (see also Inositide ISP), which (i) control gene expression and protein abundance (via chromatin re-modelling, activation of transcription factors, regulation of mRNA stability & translation and regulated protein turnover) to control proliferation, arrest and lineage commitment and (ii) regulate the cell death machinery (apoptosis, autophagy, axon degeneration) to promote cell survival or cell death.  We focus on intracellular signalling by Ca2+, phospholipids (PLD, PI3K) and protein kinases (MAPKs, SAPKs and PKB/Akt) and aim to understand how these evolutionarily conserved signalling mechanisms are controlled and how they converge on intracellular organelles (nucleus, ER, mitochondria, etc) to control cell fate decisions in response to environmental challenge.

Our work is divided into three themes.  Within these we work together on specific projects so that each theme benefits from our individual expertise, combined experience and shared information and reagents.

Theme 1. Signalling mechanisms controlling cell proliferation differentiation, senescence and survival. 

We are seeking to understand how signalling pathways (Ca2+, phospholipids and protein kinases) function and are regulated in time and space and how they control cell fate decisions through the regulation of short-term, non-genomic targets and long-term, genomic targets.  This includes the identification of new targets or effectors of these pathways (proteomics and genomics) that are responsible for influencing gene expression and/or organelle function.  Our work here covers a variety of model cell systems, including stem cells that have a high capacity for self-renewal and so allow adaptation to environmental challenge.  This is basic bioscience underpinning health and is relevant across many fields of biology, including mechanisms of cell senescence/ageing, and also informs work in Themes 2 & 3.

Theme 2. Signalling mechanisms controlling lifelong homeostasis and function of striated muscle.

 We have a strategic focus on how signalling pathways (Ca2+, ERK1/2, p38MAPK and PKB/Akt) control the maintenance and regeneration of skeletal and cardiac muscle; both are crucial to lifelong health and well-being and are progressively undermined during ageing.  Whilst skeletal muscle has the power to self-renew in response to injury (via significant stem cell activation, proliferation and differentiation), cardiac plasticity in response to exercise/stress is more dependent on hypertrophy of existing cardiomyocytes.

Theme 3. Signalling mechanisms controlling lifelong neuron survival and function. 

A major challenge in the neuroscience of ageing is that neurons are terminally differentiated cells with little regenerative capacity and yet to function effectively into old age they must adapt to a lifetime of everyday stresses and age-related changes.  Key to this is the process of axonal transport whereby essential cargoes are delivered over great distances to the synapse; when this process is interrupted (e.g., by injury) axons degenerate by a well-defined process called Wallerian degeneration.  We are interested in the role of signalling pathways (especially JNK) in axonal transport and axon survival and the wider role of PLD in the maintenance of neurites in the normal and ageing brain.

Strategic Relevance. 

Within the BBSRC Strategic Plan our work maps to Strategic Research Priority 3 – Basic Bioscience Underpinning Health.  In addition, our work maps to Grand Challenge 3 within the BBSRC Delivery Plan – Fundamental bioscience enhancing lives and improving wellbeing (lifelong health and wellbeing). In particular, the pathways we study underpin normal development and homeostasis and may be de-regulated in normal age-related disorders.

Excellence with impact – economic and social impact. 

Many of the pathways we study are de-regulated in a variety of human diseases including cardiac arrhythmias, auto-immunity, inflammation, neurodegenerative conditions and cancer, making them attractive drug targets.  To this end we translate our basic research through collaborations with charities, clinicians and biotech and pharmaceutical companies.  In this way our research is bringing new understanding of a range of medical disorders and with it the potential to develop ever more sophisticated therapeutic strategies for the prevention and management of disease.  We are also actively involved in staff development through the training of PhD students and scientists at all levels who go on to work in academia, industry and allied areas such as intellectual property management.  In this way we are training the excellent researchers and research managers of tomorrow.

Key publications from the Signalling & Cell Fate ISP

Translating the ISP's Research into Action (KEC)

Public Engagement

Skills training