Targeted Nucleose Technology and knockout rats – guest lecture at NTNU

Yesterday Professor Aron Guerts from the Cardiovascular Research Center and Human Molecular Genetics Center at the Medical College of Wisconsin visited NTNU. Many of us visited his guest lecture, titled “Targeted Nuclease Technology: Empowering genetic engineering beyond the mouse”.

Over the past five to ten years, a suite of revolutionary tools has emerged and created a new field of “Genome Editing”. During the last 20 years, precision modification of a genome was basically restricted to the mouse model and their embryonic stem cells from a couple of common strains. Scientific progressions within the field have now made it possible to engineer precise mutations and genetic modifications to essentially any genome of any cell from any strain or species.

Photo: HeadSpin

Photo: HeadSpin

With the term Targeted Nuclease Technology (TNT), Guerts especially points to the three following discoveries:

  • The Zinc-Finger Nucleases (ZFNs), an artificial restricion enzyme improving the targeting of unique sequences within complex genomes.
  • Transcription activator-like effector nucleases (TALENs) – another restriction enzyme, generated by fusing a TAL effector DNA binding domain to a DNA cleavage domain. This type of enzymes cut DNA strands at a specific secuence. The advantage of transcription activator-like effectors (TALEs) is that they can be engineered to bind practically any desired DNA sequence. This enables genome editing when TALENs are introduced into cells.
  • RNA-Guided Nucleases (RGNs) (CRISPR/Cas9), programmable endonucleases also involved in targeted genome editing. 

These discoveries have vastly expanded the possibilities for both basic research of the genome and for promising therapeutic strategies. Guert’s research group at the Medical College of Wisconsin has explored the use of TNT to laboratory rat and mouse disease model strains to create resources of gene knock-out models, specific gene knock-in strains, and for generating conditional (Cre/loxP-based) knockout models.  When combined with other transgenic tools, they are now empowering rat researchers across the globe to address gene-centered hypotheses in widely studied physiological, pharmacological, biochemical, and behavioral model systems.

Guerts is a key contributor to this exciting technology development and was responsible for the world’s first targeted gene knockout rats. For  a more thorough description, you can read about the Knockout Rats in a Science article from 2009.

Maria Henningsen, CERG

Can aerobic interval training reverse heart dysfunctions?

At our center there is a wide focus on increasing the knowledge of the mechanisms involved in heart disease, and developing methods aimed to prevent or treat disease. A recently published study by PhD student Anne Berit Johnsen and CERG colleagues provides a significant contribution to the field.

What we know from before, is that impaired cardiomyocyte contractility and Ca2+ handling is typically observed in patients with left ventricular contractile dysfunction. Further, previous studies have shown that exercise may improve the left ventricular function in patients suffering from heart failure after heart infarction. Exercise is also found to improve cardiomyocyte function and Ca2+ handling in rats with the same disease. But is there even beneficial effects of exercise on atrial myocyte function and Ca2+ handling?

heartTo explore this, contractile function and Ca2+ handling in atrial myocytes of sham-operated rats and rats with post-infarction heart failure was compared. The effects of aerobic interval training was also investigated. The results were in line with what previous research: high intensity aerobic interval training restored atrial myocyte contractile function and reversed changes in atrial Ca2+ handling in heart failure rats.

This study increases our understanding of how atrial myocyte contractile dysfunction in post-infarction heart failure is associated with major impairment in Ca2+ handling, whereas aerobic interval training can restore the dysfunction via improved Ca2+ handling. As mentioned in a previous blog post, animal studies are important steps on the way to understanding the human heart. In future studies this model can help to highlight important mechanisms behind heart failure as a substrate that promotes atrial fibrillation, and also the effect of training as a treatment.

Maria Henningsen, CERG.