Team:UIUC Illinois/Project/Background Info

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   <h3>Project</h3>
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       <li style="margin-bottom:20px;"><a href="https://2013.igem.org/Team:UIUC_Illinois/Project/Overview">Overview</a></li>
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       <li style="margin-bottom:20px;"><a href="https://2013.igem.org/Team:UIUC_Illinois/Project/Background_Info"><u>Background Info</u></a></li>  
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<p class="left"> <b>Cardiovascular disease and etiology</b><br>
 
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Many heart illnesses are deemed cardiovascular disease.  Cardiovascular disease, also known as heart disease, is the medical term used to describe a slew of heart-related health problems, including myocardial infarctions, heart failure, and stroke.  A major source of these problems is the onset of atherosclerosis, a condition characterized by the buildup of plaque in one’s arteries.  There are a variety of causes of atherosclerosis, but our project addresses the proatherogenic substance trimethylamine-n-oxide, a metabolite of certain chemicals often found in red meat and energy drinks.<br><br>
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<p class="left"> <br><b>Cardiovascular Disease</b><br>
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<b> Gut Bacteria and Atheroscelosis</b><br>
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Cardiovascular disease (CVD), also known as heart disease, has been the leading cause of death in the United States for over twenty years and is becoming a severe global health issue. Cardiovascular disease describe a slew of heart-related health problems, including myocardial infarctions, heart failure, and stroke.  A major source of these problems is the onset of atherosclerosis, a condition characterized by the buildup of plaque in one’s arteries.  There are a variety of causes of atherosclerosis, but our project addresses the proatherogenic substance trimethylamine-n-oxide, a metabolite of certain chemicals often found in red meat and energy drinks.<br><br>
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TMAO is the product of gut bacteria metabolism of L-carnitine.  L-carnitine is essential to cellular processes, and the cells of the human body produce it as needed.  It can begin to cause problems, however, when excessive amounts are present in one’s diet; typically it is found in high levels in red meat and energy drinks.  Certain strains of bacteria found in the intestines break down L-carnitine into trimethylamine.  The product trimethylamine is toxic to the human body and is therefore broken down by the liver into trimethylamine-n-oxide.<br><br>
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<b> Intestinal Microbiota Promotes Atherosclerosis</b><br>
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<b>Current Treatments</b><br>
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Meat consumption correlates to high risk of Cardiovascular disease (CVD), mostly because the high level of fats and cholesterol in diet may promote atherosclerosis.  Recent research concluded that those two factors may not be sufficient in establishing the link between meat consumption and CVD risk.  Researchers in Cleveland Clinic found that intestinal microbiota (gut bacteria) metabolize dietary L-carnitine into trimethylamine (TMA), which is further converted to trimethylamine-N-oxide (TMAO) and accelerates atherosclerosis in mice. <br><br>
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The best way to avoid TMAO-induced atherosclerosis is to exercise moderation when consuming red meat and energy drinksHowever, self-control alone is not the most effective method for promoting public health.  There are no treatments to directly reverse the buildup of plaque once it has imbedded itself in the walls of arteries. In severe cases, bypass surgeries and stents are used to redirect and manage blood flow through the body.  These procedures are rather invasive and come with long recovery times.  The University of Illinois (UIUC) iGEM Team sought a better method for people to be able to eat the food they love while maintaining a healthier heart.<br> <br>
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L-carnitine plays an essential role in the generation of energy in cells due to its function in transporting fatty acids from the cytosol into the mitochondriaFor this reason it is sometimes sold in the form of "food supplements" and is marketed as a "natural" health productHowever, for normal healthy adults, the cells of the human body produce sufficient amounts of L-carnitine as needed. They also analyzed 2,595 cases of patients who were undergoing cardiac evaluation, and found out a increased rate of cardiac events among those patients with high plasma L-carnitine levels and high TMAO levels.<br><br>
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<b> Gut Bacteria Ecology and Intervention</b><br>
 
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Most current treatments of atherosclerosis are not preventative.  Our team looked to provide one such preventative treatment by halting the production of TMAO.  Thousands of gut bacteria reside within the human digestive tract, and some L-carnitine loving bacteria found in the flora are responsible for converting L-carnitine into TMA. <br>
 
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Our strategy for combating the production of TMA is to make a probiotic that will outcompete the current gut flora for L-carnitine.  This probiotic will then process the L-carnitine into a much less harmful product.<br><br>
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<b>Current Solutions</b><br>
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<b>Genetically Modified Nissle 1917</b><br>
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Current approaches in treating CVD are invasive and come with long recovery times, therefore it would be ideal to start from prevention. The best way to avoid microbiota-dependent atherosclerosis is through diet control and also exercise. However, self-control alone is not the most effective method for promoting public health. Specific to microbiota dependent atherosclerosis, researchers have reported that multiple bacterial strains in gut have different capacity in metabolizing L-carnitine and produce TMA, therefore it is difficult to target and eliminate them. So current suggestion is to inhibit the activity of gut flora by ingesting antibiotic cocktail. However, this method is far from satisfying. Because antibiotic pressure might lead to a selection of "super bacteria", which has multiple resistance to antibiotics and might do harm to our body and can't be killed. Also, the activity of gut flora is considered beneficial to host in various aspects, therefore it is crucial to keep a balance of the bacteria composition.<br> <br>
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Safety is always a major concern when introducing foreign organisms into the body, so we have chosen to work with Escherichia coli (E. coli) strain Nissle 1917 to start the platform of creating a safe probiotic.  The Nissle strain is deemed safe-for-consumption and probiotic use by the United States Food and Drug Administration.<br>
 
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E. coli has a natural L-carnitine uptake system, but to outcompete the pre-existing gut bacteria, we decideded to genetically modify our strain.  The genes CaiX and CbcVW were selected to be implemented into our bacteria from Pseudomonas Aeruginosa, a bacterium with unique adaptations for L-carnitine uptake and processing.<br>
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<b>Chassis: <i>Escherichia coli</i> Nissle 1917</b><br>
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Additionally, in order to break down the L-carnitine, we introduced the CDH gene from P. Aeruginosa into our Nissle cells. This gene encodes for L-carnitine dehydrogenase, a protein that metabolizes L-carnitine along a safer alternative pathway.<br><br>
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Safety is always a major concern when we talk about bacteria based treatment, so we have chosen to work with <i>Escherichia coli</i> strain Nissle 1917 as the platform for creating a safe probiotic. Claimed by manufacturer of its commercial form "Mutaflor", Nissle 1917 is "one of the best-examined and therapeutically relevant bacterial strains worldwide". <i>E. coli</i> Nissle 1917 has been widely tested for more than 80 years, mostly as a drug deliver system. The strain has T7 RNA Polymerase, which can transcribe DNA downstream of a T7 promoter. <br><br>
<b>Our Solution: Cardiobiotics</b><br>
<b>Our Solution: Cardiobiotics</b><br>
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With our genetic parts, our Cardiobiotics present a never-before-seen application of synthetic biology to the field of cardiovascular health.  Our engineered bacteria can uptake L-carnitine and divert it along pathway toward the end product of glycine-betaine, a much less harmful product than TMAO.</p>
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Based on the finding that chronic ingestion of carnitine-riched food will cause the composition change in gut flora, specifically induced the thrive of L-carnitine loving bacteria, the UIUC-Illinois iGEM Team developed a better strategy to construct a probiotic that will out-compete the current gut flora for L-carnitine. With our genetic parts, our genetically modified Nissle 1917, named as Cardiobiotics, presents a never-before-seen application of synthetic biology to the field of cardiovascular health.  This summer, Cardiobiotics was tested effectively uptake L-carnitine and diverted to the pathway leads to 3-dehydrocarnine.</p>
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For <b>references</b> please see <a href="https://2013.igem.org/Team:UIUC_Illinois/About/Attributions">attributions.</a><br>
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Latest revision as of 03:51, 28 September 2013

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Cardiovascular Disease
Cardiovascular disease (CVD), also known as heart disease, has been the leading cause of death in the United States for over twenty years and is becoming a severe global health issue. Cardiovascular disease describe a slew of heart-related health problems, including myocardial infarctions, heart failure, and stroke. A major source of these problems is the onset of atherosclerosis, a condition characterized by the buildup of plaque in one’s arteries. There are a variety of causes of atherosclerosis, but our project addresses the proatherogenic substance trimethylamine-n-oxide, a metabolite of certain chemicals often found in red meat and energy drinks.

Intestinal Microbiota Promotes Atherosclerosis
Meat consumption correlates to high risk of Cardiovascular disease (CVD), mostly because the high level of fats and cholesterol in diet may promote atherosclerosis. Recent research concluded that those two factors may not be sufficient in establishing the link between meat consumption and CVD risk. Researchers in Cleveland Clinic found that intestinal microbiota (gut bacteria) metabolize dietary L-carnitine into trimethylamine (TMA), which is further converted to trimethylamine-N-oxide (TMAO) and accelerates atherosclerosis in mice.

L-carnitine plays an essential role in the generation of energy in cells due to its function in transporting fatty acids from the cytosol into the mitochondria. For this reason it is sometimes sold in the form of "food supplements" and is marketed as a "natural" health product. However, for normal healthy adults, the cells of the human body produce sufficient amounts of L-carnitine as needed. They also analyzed 2,595 cases of patients who were undergoing cardiac evaluation, and found out a increased rate of cardiac events among those patients with high plasma L-carnitine levels and high TMAO levels.

Current Solutions
Current approaches in treating CVD are invasive and come with long recovery times, therefore it would be ideal to start from prevention. The best way to avoid microbiota-dependent atherosclerosis is through diet control and also exercise. However, self-control alone is not the most effective method for promoting public health. Specific to microbiota dependent atherosclerosis, researchers have reported that multiple bacterial strains in gut have different capacity in metabolizing L-carnitine and produce TMA, therefore it is difficult to target and eliminate them. So current suggestion is to inhibit the activity of gut flora by ingesting antibiotic cocktail. However, this method is far from satisfying. Because antibiotic pressure might lead to a selection of "super bacteria", which has multiple resistance to antibiotics and might do harm to our body and can't be killed. Also, the activity of gut flora is considered beneficial to host in various aspects, therefore it is crucial to keep a balance of the bacteria composition.

Chassis: Escherichia coli Nissle 1917
Safety is always a major concern when we talk about bacteria based treatment, so we have chosen to work with Escherichia coli strain Nissle 1917 as the platform for creating a safe probiotic. Claimed by manufacturer of its commercial form "Mutaflor", Nissle 1917 is "one of the best-examined and therapeutically relevant bacterial strains worldwide". E. coli Nissle 1917 has been widely tested for more than 80 years, mostly as a drug deliver system. The strain has T7 RNA Polymerase, which can transcribe DNA downstream of a T7 promoter.

Our Solution: Cardiobiotics
Based on the finding that chronic ingestion of carnitine-riched food will cause the composition change in gut flora, specifically induced the thrive of L-carnitine loving bacteria, the UIUC-Illinois iGEM Team developed a better strategy to construct a probiotic that will out-compete the current gut flora for L-carnitine. With our genetic parts, our genetically modified Nissle 1917, named as Cardiobiotics, presents a never-before-seen application of synthetic biology to the field of cardiovascular health. This summer, Cardiobiotics was tested effectively uptake L-carnitine and diverted to the pathway leads to 3-dehydrocarnine.

For references please see attributions.