Team:NTU-Singapore/Project

The Problem

The NTU iGEM '09 Team has identified atherosclerosis as the problem we would like to tackle.

Atherosclerosis is one of the major diseases affecting the world. In our research, we found the numbers were staggering, and growing. We also found that early diagnosis was rare, medications were not ideal and surgeries were a commonly used last resort.

We asked ourselves what if we could design a biological system to identify plaque sites and reduce the plaque volume in vivo?

Atherosclerosis in physiology

Here's an informative video describing the nature of atherosclerotic buildup, and the deadly consequences.

As you can see, LDL-cholesterol buildup, and subsequent foam cell formation is the root cause of plaque buildup.

The condition becomes increasingly irreversible as calcification sets in.

The problem then is that plaque buildup is not identified early enough for medication to actually reverse the condition, rather than alleviating the symptoms.

Our solution is to target the early stages of plaque build-up. Our system needs to sense potential atherosclerotic sites, and immediately breakdown components of buildup, as well as help in the early diagnosis.

Symptoms & bodily reactions

In our research and literature review, we identified the following characteristics of plaque buildup. We can hope to specifically identify plaque sites with these symptoms, and exploit some of these mechanisms in the biological system we plan to build.

• Intuitively, we understand that decreased lumen area due to plaque leads to faster flow rate of blood.
  • How can our proposed biological system stay at the problem site long enough to effect any action?

• Fortunately, research shows that damaged arterial endothelium exhibits p-selectin abundantly at the lumen surface to signal for help.
  • This p-selectin attaches firmly and strongly to naturally occuring PSGL-1 protein-ligands in activated platelets.
  • If need be, we can engineer our system to express PSGL-1 on its surface to selectively bind to p-selectin at damaged sites.

• Research indicates that damage to arterial endothelial cells decreases local levels of nitric oxide (NO) in blood.
  • We can use this as a trigger to switch on our system.

• On a tangential note, NO is also a known vasodilator.
  • We identify NO as both the trigger to start as well as the feedback stimulus to stop our system.

• We find that the lipid core in foam cells are in the form of oxidized cholesterols, ie. cholesteryl esters.
  • If we can target these for enzymatic degradation, it will decrease the size/volume of the buildup.

• Diagnosis of plaque is usually done in late-stage. One reason is the gradual rate of buildup which only exhibits symptoms in the later stages.
  • It would be useful if our biological system can, in some way, to allow for plaque site identification and imaging.
  • Tsien Lab recently discovered the infrared protein (IFP), which can be used in infrared imaging of mammalian systems.
    • What if we can engineer our system to include IFP for atherosclerotic imaging?

References/Literature