Team:Siberia

Welcome to Siberia team wiki!

We are the first iGEM team from Siberia and we are going to defy obesity working on our project

LEAP2BRAIN

This is how our project is called. What is the idea?

We thought long and hard about what problem we should tackle with the help of synthetic biology. What is currently relevant? What can we realistically and successfully do in the limited four-month timeframe, that is still ambitious and challenging? The choice fell on the treatment of obesity with living therapeutics. Our attention was drawn to LEAP-2, a rather interesting protein, which is able to regulate appetite and satiety, thereby influencing human eating behaviour. For a therapeutic effect, this protein must be periodically supplied directly into the brain.

Here is the gist of our project: we are planning to create a strain of bacteria that produces LEAP-2, which can be implanted into a person's nose for constant synthesis of the desired product. With this approach, the protein will be delivered directly to the brain via the olfactory and trigeminal nerves, bypassing the bloodstream and the blood-brain barrier.

The overall goal of our project is to provide a proof of concept for the development of living therapeutics working on the principle of nose-to-brain delivery. We have plans to test our system on mice and hope to present our first results during the course of the competition!

As we've said in our introductory post, the main idea of our project is to create a bacterium that will secrete LEAP2 into the nose, after which the protein will travel to the hypothalamic region of the brain via the trigeminal nerve, and bind to a receptor of the hormone Ghrelin (GHSR1a).

So, why did we choose LEAP-2? In the early stages of project development, it actually caught our attention because of its recently discovered physiological effect. Several studies have shown that an increase in the ratio of LEAP2/Ghrelin concentration in the blood will be beneficial for weight loss, due to an onset of a feeling of satiety and hence a decrease in food intake. To visualize the protein secreted by the bacterium, we decided to use an epitope of the C-myc protein — Myc-tag, and to facilitate its entry into the brain — a cell-penetrating peptide called Low molecular weight protamine. Combined with a Myc-tag and LMWP, the fusion protein will have a length of 65 amino acids, and we hope that the small size will facilitate secretion from the bacteria.

Though we are not planning on demonstrating the physiological effect of the protein, we carried out in silico modelling of the putative structure of the fusion protein to ensure that the Myc-tag and the N-terminus are open, since according to various sources, the first 10-14 amino acids are sufficient for binding to the GHSR1a receptor.

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Tips

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Inspiration

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