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.

It is clear then that early stage diagnosis and treatment will be more effective & beneficial.

Symptoms & Present treatments

Atherosclerotic plaque buildup is a gradual process. It doesn't help that the body accommodates for any changes, hence delaying the onset of symptoms until it's too late. Symptoms themselves vary depending on which arteries exactly the plaque buildup is in.

Symptoms include:

• If in arteries closer to the heart
  • Chest pain (angina) &
  • other complications similar to heart attack conditions

• If in arteries leading to the brain
  • Sudden numbness/weakness in limbs
  • Slurred speech
  • Drooping facial muscles etc.

• If in arteries leading to limbs
  • intermittent claudication (leg pain)

As such, present medications are catered largely toward immediate relief of symptoms, and less on reversing the condition. Unfortunately, the medication is also accompanied by the need for a complete lifestyle change to prevent the problem from getting worse.

Medications include:

• Anti-coagulants
• Anti-platelets
• Beta-blockers
• ACE inhibitors &
• other cholesterol medications.

More often that we would prefer, surgery becomes a necessary option due to the late-stage urgency. These are major surgeries, that will have drastic impacts on lifestyle and quality of life thereafter.

Surgical techniques include:

• Coronary angioplasty
• Bypass surgery (including open-heart surgery)
• Stent placement &
• Carotid artery surgery

As you can see, none of these options are particularly appealing.

Characteristic bodily reactions

In our research and literature review, we identified the following characteristics of plaque buildup.

• Intuitively, we understand that decreased lumen area due to plaque leads to faster flow rate of blood.

• Research shows that damaged arterial endothelium exhibits p-selectin abundantly at the lumen surface to signal for help.
  • This p-selectin binds selectively to p-selectin glycoprotein ligand (PSGL-1) via natural catch-bond mechanism, which works best in fast-flowing conditions.

• Research indicates that damage to arterial endothelial cells leads to decreased local levels of nitric oxide (NO) in blood.
  • On a tangential note, NO is also a known vasodilator.

• We find that the lipid core in foam cells are in the form of oxidized cholesterols, ie. cholesteryl esters.
  • The body is not able to break down cholesterol found in this form.

• Diagnosis of plaque is usually done in late-stage due to delayed symptoms.
  • Reasons include the gradual buildup of plaque & bodily adjustment to initial stages of plaque buildup .

We hope to specifically identify plaque sites with these symptoms, and exploit some of these mechanisms to build our biological system.

Engineering a solution

From this list of characteristics, we will try to describe a solution that caters specifically to alleviating the atherosclerotic condition.

Our solution will factor in an intimate understanding of the anatomy of the plaque site, as well as the bodily adaptations to such damage. We will design our solution to work in vivo taking advantage of bodily signals and mechanisms to reduce the plaque buildup. Please proceed to System Specifications to see our solution.

References/Literature