Dr Jan Czyzyk explores the biomolecules serpins, and how serpin activity can affect the inflammation and tissue regeneration of cells in the pancreas. Their research opens the possibility for anti-serpin activity to be used as both a biomarker and an active mechanism of protection for individuals with type 1 diabetes.
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Read the original article: https://www.doi.org/10.1126/scitranslmed.abf1587
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Hello and welcome to Research Pod! Thank you for listening and joining us today.
In this episode we will be looking at the research of Dr Jan Czyzyk at the University of Minnesota. Together with his research team, Czyzyk explores the biomolecules: serpins. They are interested in how serpin activity can affect the inflammation and tissue regeneration of cells in the pancreas. Excitingly, their research opens the possibility for anti-serpin activity to be used as both a biomarker and an active mechanism of protection for individuals with type 1 diabetes.
Although it’s sometimes uncomfortable and painful while experiencing it, inflammation is a vital process of the human body. It’s how the body responds to harmful stimuli such as pathogens, damaged cells, or irritants. The goal of inflammation is to eliminate the cause of injury, clear away dead cells, and initiate the process of tissue regeneration.
Tissue regeneration is the other side of the same process. It involves the renewal and restoration of biological tissues. All living things are capable of some form of tissue regeneration – although some species have a far greater capacity for it than others. The regenerated tissue can be the same as the old tissue, or partially the same if the original tissue damage was too great.
Recent work by Dr Jan Czyzyk and his team at the University of Minnesota explores this balance between inflammation and tissue regeneration. Specifically, they’re interested in the inflammation and tissue regeneration of pancreatic islet cells – the groups of cells within your pancreas that produce the hormone insulin, which regulates blood sugar levels.
Their research suggests that certain types of activity detected in humans could be used as both a biomarker and as an active mechanism of protection from type 1 diabetes.
Firstly, though, to understand their findings it’s important to be aware of a further balancing act within the body: that of proteases and serpins.
With most of the processes within the human body, balance is key, and knocking this balance one way or the other can have serious consequences. The equilibrium between inflammation and tissue regeneration is mediated by proteases, and anti-protease inhibitors, called serpins.
Proteases are enzymes that speed up the breakdown of proteins into smaller molecules. They do this by ‘cleaving’ the peptide bonds within the proteins via hydrolysis – a reaction where bonds are broken by water. Conversely, serpins work to inhibit proteases, by permanently altering the shape of their active site, that is, the place where enzymes bind to molecules.
The action of serpins is important: if proteases are left uncontrolled and run rampant, high levels of protease activity can cause a lot of damage to the body. A low level of protease activity is key to the survival of all multicellular organisms, including humans. However, this doesn’t mean proteases are ‘bad’ to have in your body; they’re an essential part of life – they just need to be properly mediated.
Type 1 diabetes is an autoimmune disease where little to no insulin is produced by the islet cells of the pancreas. Our bodies use insulin to regulate the levels of glucose in the bloodstream, so if the disease is left untreated, people with type 1 diabetes are left with very high levels of sugar in their blood. They then suffer from symptoms such as weight loss, thirst, and tiredness. Diabetes needs to be managed throughout the rest of the person’s life, either through regular insulin injections or with an insulin pump.
Czyzyk and his research team used type 1 diabetes as a model of autoimmune disease in their studies. They successfully demonstrated that protease activity cleaves the surface molecules expressed in inflammatory cells that accumulate in pancreatic islets. Essentially, the proteases cut away the small proteins coating the surfaces of these cells.
By doing so, this impairs the function of the inflammatory cells and helps to lower inflammation within the pancreatic islets. In turn, Czyzyk’s team showed that these changes can delay the clinical onset of type 1 diabetes in an animal model.
More recent studies from Czyzyk’s lab show a further interesting development.
Protease activity can help to generate additional cells that are able to produce insulin in the pancreas. Under normal conditions, a molecular system called the ‘Notch signalling pathway’ is responsible for keeping stem cells in an undifferentiated state.
The Notch signalling pathway is present in most living animals. It involves the action of four receptors that play a major role in embryonic development as well as promoting neurogenesis – the process by which nervous system cells are produced from stem cells.
Researchers believe that the Notch pathway also plays an important role in the development of the pancreas, specifically, the recruitment of endocrine cells from a common precursor. Endocrine cells make up the glands that produce hormones.
In work recently published in Science Translational Medicine, Czyzyk’s team show that certain proteases were able to disengage this Notch signalling process, which in turn accelerates the development of insulin-producing cells from undifferentiated early stem cells. This could be a valuable discovery, as boosting the number of these cells within the pancreas could help to make people more resistant to type 1 diabetes.
Many of Czyzyk’s studies have been performed with an antibody that is known to inhibit a specific serpin, called serpin B13.
By using an antibody that binds to this molecule, the researchers found that they can block its inhibitory function. The knock-on effect of this is an indirect stimulation of proteases and increased protease activity.
The researchers used an in vitro culture system of isolated pancreatic islet cells and added serpin B13 as well as the antibody for serpin B13.
When the antibody was added to the pancreatic islet cells, serpin B13 activity was reduced. The resulting effect was that the activity of cathepsin L increased. This is the protease that serpin B13 normally blocks.
In turn, a boost in the activity of cathepsin L protease led to an increase in cellularity of pancreatic beta-cells that produce insulin.
By adding the right dose of the antibody at the right moment, inflammation can be reduced and consequently beta-cellularity boosted.
Notably, the researchers’ findings offer a practical approach to the therapy of inflammation and tissue regeneration in type 1 diabetes. In addition, the therapy could potentially be applied to other diseases that affect tissues with high expressions of serpin and Notch.
The most exciting part of Czyzyk’s studies is the potential to translate the findings to help people at high risk of type 1 diabetes.
The researchers found that children who are at high risk for type 1 diabetes, and are positive for the autoantibody to serpin B13, do better clinically than those without the antibody. Children with the serpin B13 autoantibody tend to develop diabetes at a lower frequency.
A further study showed that anti-serpin B13 autoantibodies from humans function in a similar way to a mouse antibody to serpin B13. Interestingly, the mouse antibody to serpin B13 can stimulate the development of endocrine progenitor cells in the mouse pancreas. This suggests that the same process occurs in humans.
Czyzyk’s studies suggest that detecting anti-serpin activity within humans could be used in two ways. Firstly, it could be used as a biomarker to offer doctors clues as to whether children are at high risk of developing type 1 diabetes. Secondly, there’s the possibility of it being used as an active mechanism to protect people from type 1 diabetes.
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