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The impact of cellular senescence on astrocyte metabolism

Primary Supervisor: Dr Eric Hill, Life & Health Sciences

Secondary Supervisor: Dr James Brown, Rhein Parri

PhD project title: The impact of cellular senescence on astrocyte metabolism

University of Registration: Aston University

Project outline:

Under ‘normal’ circumstances brain homeostasis is maintained by the interaction between neurons and glial cells. However, should these mechanisms fail brain function can be significantly perturbed.

During the aging process, senescent cells accumulate, and are associated with a Senescence associated secretory phenotypes (SASPs). SASP comprises a number of cytokines, growth factors and other proinflammatory mediators, and, can bring about inflammation mediated senescence in neighbouring cells and can induce metabolic dysfunction.

As we age the numbers of senescent astrocytes are found to increase in the brain (1). Astrocytes represent a complex and functionally diverse population of cells which are recognised to be intimately involved with neuronal signalling. Some extend numerous processes that connect the blood vessels via end-feet to the neurons and the extracellular space, and ensheath synapses. They also interconnect with adjacent astrocytes via gap junctions to form an astrocytic syncytium and

(2). The secretion of SASP by senescent astrocytes can trigger inflammation in neighbouring cells and may alter normal astrocyte function. It is

therefore essential to determine the impact of SASP on neuron-astrocyte function.

Recently there has been a revolution in the field of stem cell research. Now it is possible to take skin cells from patients, transform them into induced pluripotent stem cells (iPSC), and from these generate patient specific neuronal networks in culture.

This project will provide a better understanding of brain ageing by investigating the impact of cellular senescence on human iPSC derived neuronal networks. This is needed before effective treatments can be developed to improve the ageing population’s health span.

Aims & Objectives:

The aim of this project is to investigate the impact astrocyte senescence on astrocyte metabolism. We hypothesise that induction of cellular senescence in astrocytes will induce the release of SASP that will accelerate the induction of senescence in neighbouring cells and impact upon astrocyte-neuron coupling.

Objectives:

  1. Induction of senescence astrocytes.
  2. Analysis of cellular metabolism including any dysregulation of carbohydrate metabolism
  3. Determine the inflammatory phenotype of senescent astrocytes.
  4. Asses the secretome of senescent astrocytes and its impact on neighbouringcells.
  5. Determine impact of senescence on astrocyte calcium signalling.

References:

  1. Pertusa, M.; García-Matas, S.; Rodríguez-Farré, E.; Sanfeliu, C.; Cristòfol, R. Astrocytes aged in vitro show a decreased neuroprotective capacity. J. Neurochem. 2007, 101, 794–805.

  2. Magistretti, P.J. (2006) Neuron-glia metabolic coupling and plasticity. J. Exp. Biol., 209, 2304–2311

BBSRC Strategic Research Priority: Integrated Understanding of Health: Ageing

Techniques that will be undertaken during the project:

  • Stem cell culture
  • Biochemical assays
  • Cell viability analysis
  • Microscopy
  • ELISA
  • Western blotting
  • Calcium imaging
  • qPCR

Contact: Dr Eric Hill, Aston University