Defining glucocorticoid receptor interactions with the Poly-(ADP-ribose)Polymerase, PARP-1

Craig Doig, Nottingham Trent University

 

Aims

Glucocorticoids (GC’s) are widely used for their potent anti-inflammatory effects. However, chronic glucocorticoid receptor (GR) activation leads to whole-body metabolic dysfunction and a profound loss of skeletal muscle mass. As a result, individuals exposed to chronic excess GC levels experience a progressive decline of physical strength  and overall metabolic health. In order to alleviate these detrimental outcomes a better understanding of the molecular processes governing GR transcriptional activation is  required.

Amongst the identified interacting GR proteins is the DNA Damage Repair response enzyme Poly-(ADP-ribose)polymerase 1 (PARP-1). My laboratory has generated preliminary data demonstrating PARP-1 is a novel regulator of skeletal muscle steroid hormone metabolism. This ongoing work has enabled me to generate the hypothesis: PARP-1 influences GR activity and co-regulates GC transcriptional responses within skeletal muscle. 

To challenge the hypothesis this project will use the C2C12 muscle cell line to study the following aims:

1. Establish PARP-1 impacts upon the expression of GR target genes in response to glucocorticoids.
2. Define the influence of PARP-1 upon GR’s ability to occupy genomic binding sites

Improving our knowledge surrounding the molecular actions of GR and its associated proteins can lead to treatment strategies aimed at reducing detrimental impacts of chronic GR activation.

 

Evaluation

The funding of this project has enabled me to achieve some key milestones in my academic career. These have sustained my career trajectory, this has been particularly key during COVID-19. To be clear without this award the impact of COVID-19 would have been significantly detrimental. With this award I was able to hit the ground running upon end of the COVID-19 lockdown.

Specific outcomes because of this award are listed below:

Conferences

• Physiology Annual Conference 2021 Online - Oral Communication.
• British Endocrine Society Conference Edinburgh - 2021 Poster.
• ENDO2022 Atlanta Georgia – Oral Communication. 

Published Article

• Tan et al. Cell Death & Discovery 2023 PARP1 mediated PARylation contributes to myogenic progression and glucocorticoid transcriptional response. PMID3707471.

Grant applications this work has contributed towards:

• Royal Society Research Grant £70,000  (Rejected)
• Academy of Medical Sciences Springboard Award £120,000 (Decision pending)
• Ministry of Defence Research Grant £143,000 (Awarded)

 

Grant approved: £4,750