Timely Announcement for Nobel Prize

 

Last Monday while in Amsterdam with my Mam and two sisters, a friend of mine sent a text to let me know that the 2017 Nobel Laureates in Physiology and Medicine were Hall, Rosbash and Young.  They were awarded the Nobel for their work in identifying the key genes that create circadian or body clock rhythms in the fruit fly. My feet literally were stuck to the ground, it was thrilling to know that these gentlemen would get the recognition that they so deserve, but also what this will mean for the field of science that I am so passionate about. The body clock is the molecular timekeeping system that exists in practically every organism on the earth and in every cell in our body. Simply put, it allows the cell to tell what time of day it is. Why is that important? We live on a spinning planet and because of the earth’s rotation to the sun, all life on earth has been subjected to daily periods of light and heat, dark and cold. The body clock allows us to anticipate and respond to these 24-hour predictable environmental changes and synchronises our physiology to it. For example, the body clock increases cortisol levels in the body ahead of awakening, this helps us to become active once we wake. The body clock also increases expression of digestive enzymes in the intestinal tract during daylight hours (this is why curry chips at 3am is never a great idea!).

Back in the 80’s Hall, Rosbash and Young independently isolated a gene called Period, they showed how the gene encodes a protein PER that builds up in cells at night and degrades during the day. This daily rise and fall of PER essentially allow the cell to track time of day. How thrilling it must have been for them to observe this daily change in the mRNA levels of Period gene (Figure 1- black line), all that is changing along the x-axis is the time of day.

So what does this mean three decades later? We have made great strides in understanding how the molecular clock works. We now know that the clock keeps time by a series of transcriptional-translational feedback loops. We also know that the clock controls 40% of all coding genes within the body. The body clock controls all aspects of our physiology from metabolism to immunity.

Many diseases, such as osteoarthritis and cardiovascular disease, are highly time of day dependent. Moreover, it appears that disruption of our body clocks, caused by our non-stop 24/7 lifestyle and exposure to artificial light at all times of day, is partly responsible for the increase in chronic inflammatory diseases. Unfortunately, most cell culture systems are not synchronized with the time of day, and this, in my opinion, is one of the main reasons that many researchers unknowingly neglect this field. Finally, we are making great strides in attempting to time specific treatments to the right time of day, an area called chronotherapy. Therefore, it is my hope that this increased awareness of the body clock will bring more researchers into this fascinating field. If we don’t fully understand how our body clock controls physiology and disease we will certainly be left in the dark.

Annie Curtis is a Research Lecturer and runs the Immune Clock laboratory at MCT and is fascinated by all things body clock related.

 

The circadian protein BMAL1 in myeloid cells is a negative regulator of allergic asthma

Asthma is of particular relevance to the area of circadian control of immunity, since it is a disease with very strong clinical evidence demonstrating regulation by circadian variation. Airway hypersensitivity and asthma attacks are more common at night in humans. The molecular basis for this is unknown and no model of asthma in animals with genetic distortion of the molecular clock exists.

Asthma is under strong circadian variation. Asthma symptoms worsen at night, particularly in the early hours of the morning. Lung function fluctuates in healthy individuals over 24 h period and these fluctuations are even more pronounced in asthmatics.

In this study, we showed that mice lacking the main clock transcription factor BMAL1 in myeloid cells have increased lung inflammation demonstrated by higher numbers of eosinophils and increased IL-5 (key pathogenic cytokine in asthma that recruits eosinophils).This suggests that Bmal1 is a potent negative regulator, in myeloid cells in the context of allergic asthma. Our findings might explain the increase in asthma incidents during the night in humans when BMAL1 expression is low.

Dr. Zbigniew Zaslona from TCD (pictured here) was the lead author on the study. Both Dr. Annie Curtis (MCT) and Prof. Luke O’Neill (TCD) were joint senior authors on the paper.

The circadian protein BMAL1 in myeloid cells is a negative regulator of allergic asthma.

Zaslona Z, Case S, Early JO, Lalor SJ, McLoughlin RM, Curtis AM*, O’Neill LA* – Both authors contributed equally to this study.

Am J Physiol Lung Cell Mol Physiol. 2017 Mar 23:ajplung.00072.2017. doi: 10.1152/ajplung.00072.2017. [Epub ahead of print]

The Immune-Clock laboratory of Dr. Annie Curtis, a recent recruit to RCSI

MCT Research Talks – 30th January 2017

Last week’s departmental talks encompassed a Deep Dive into Clock biology in Macrophages affecting the Inflammatory Response. This area is the focus of the Immune-Clock laboratory of Dr. Annie Curtis, a recent recruit to RCSI.

Jamie Early, my PhD student

Jamie Early (PhD student of the Curtis Lab) currently residing in the Luke O’Neill Laboratory presented his findings on the role of the circadian clock in suppressing inflammation in macrophages and if the anti-oxidant transcription factor and redox sensor NRF2 plays a role. His talk was titled ‘The macrophage clock is a key controller of the anti-oxidant and inflammatory response via the transcription factor Nrf2’.

Second up, we had Mariana Cervantes (PhD student and visiting scientist from the Instituto Politecnico Nacional (IPN) in Mexico) present her talk titled ‘The macrophage clock is having a profound impact on mitochondrial dynamics- what are the implications for inflammation?’

Mariana Cervantes

Mariana is interested in how mitochondria alter their morphology, either fusing together to form networks or fragmenting into smaller units termed fission. She is trying to uncover if the clock is regulating this process and if so what are the implications for the inflammatory response.

This work is part of a collaboration between RCSI and  Luke O’Neill laboratory at TCD and is funded through Science Foundation Ireland

Immunometabolism, Is it under the eye of the clock

Annie Curtis reports

Our Immune-clock laboratory has a real interest in metabolism and how alterations in metabolic pathways termed “metabolic reprogramming” can shape the type of immune response. This area called “Immunometabolism” has exploded in the last 5 years, and the implications are massive. It appears that macrophages use one metabolic pathway to become highly proinflammatory and another metabolic pathway to resolve inflammation and promote wound healing.  So why is our laboratory so interested in this? Well, if you think about daily changes in our environment, the two biggest are the sleep/wake cycle and the other is feeding/fasting. It is now clear that clocks in metabolic tissues like the liver/pancreas/adipose tissue prepare the body to deal with this daily rhythm in feeding/fasting. Based on this, our interest is to figure out if the clock within macrophages is somehow altering its metabolism over the course of the day and is that leading to changes in macrophage function, particularly the inflammatory response.

Jamie Early, my PhD student

Jamie Early, my PhD who “lives” in Prof. Luke O’Neills laboratory at TCD and I were invited to submit this first ever review on circadian immunometabolism, and you can find it here.

Additional reading

  1. Early JO, Curtis AM Immunometabolism: Is it under the eye of the clock?Semin Immunol. 2016 Oct;28(5):478-490

Follow me on Twitter @curtisannie

Its about Time! The role of body clocks in health and disease

Annie Curtis reports

How metabolic and immune parameters vary across the 24 hours (1).

Body clocks tend to garner quite a bit of attention from the media. Folks are obsessed with sleep, either they cant get enough or they are getting too much, and all of us can relate to the symptoms of jet lag and morning versus evening types. Therefore it’s a great topic to discuss with wider audiences. I really enjoy chatting with people about the implications of our internal timing system and that research now shows that living in synchrony with your body clock can improve overall health. For the SFI Science week I was asked to provide an interview to the Daily Star called “The Science of Sleep Explained”. I was also asked to go on the “Alive and Kicking” show on Newstalk Radio with Ciara Kelly, you can listen to the interview: What type of sleeper are you? Are you an owl or a lark?

Additional reading:

  1. Early JO, Curtis AM Immunometabolism: Is it under the eye of the clock?Semin Immunol. 2016 Oct;28(5):478-490

Annie Curtis on Twitter @curtisannie