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, up to 7.2 million people are affected by coronary artery disease alone; a majority of these are caused by atherosclerosis. In most cases, diagnosis is rare, medications are not ideal and surgeries are a commonly used last resort.

Our goal is to identify plaque sites and degrade the lipid core in vivo using a biological system.

Atherosclerosis in physiology

Atherosclerosis is an inflammatory disease caused by the buildup and hardening of fatty deposits on arterial walls. This accumulation eventually restricts the blood flow through the affected vessels.

The condition starts with damage to arterial endothelium by risk factors like high blood pressure, high cholesterol, irritants like nicotine etc. The initial damage is then aggravated into an inflammatory condition by platelet clumping.

This disruptive accumulation facilitates the accumulation of fatty deposits (oxidized LDL-cholesterol) and other cellular waste products. Special white blood cells that engulf the cholesterol derivatives, are unable to break them down. Hence these white blood cells become foam cells. Over time, all this debris hardens into a plaque.

The plaque proceeds to grow until the vessel's lumen becomes increasingly obstructed, leading to severe complications due to reduced blood flow.

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 that early stage diagnosis and treatment of atherosclerosis will be more effective & beneficial than late stage treatment.

Symptoms & Present treatments

Atherosclerotic plaque buildup is a gradual process. It does not 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 develop.

Symptoms include:

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

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

• for 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.

To see our proposed solution, please proceed to System Specifications.

References/Literature

See the complete list of references here.