How are beneficial cholesterol transport proteins produced?
Abstracts
Initial Award Abstract |
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Cigarette smoking is one of the major risk factors for coronary and peripheral vascular disease. Users of tobacco have a 2.5 fold higher prevalence of elevated blood cholesterol (hypercholesterolemia) than non-smokers, which further increases their risk for cardiovascular disease. As a dietary fat that is also made by the body, cholesterol is not soluble in the blood and must be carried in the blood stream via several fat-transporting proteins. One of these proteins is apolipoprotein B (apo-B), which is found in two different sizes in human blood: the large apo-B100 and the smaller apo-B48. Several studies that focused on reducing blood cholesterol levels demonstrated that it beneficially corresponds with having relatively lower amounts of apo-B100 in blood. The larger apo-B100 is produced by the liver while the smaller apo-B48 is formed in the intestines from a mutated (i.e., edited) form of the same genetically-coded signal molecule (messenger RNA or mRNA) that is used to produce the larger apo-B100. This specialized mutating or "editing" process is carried out by several enzymes called an "editing complex". Whenever the apo-B mRNA comes into contact with this editing complex, the apo-B mRNA is transformed, resulting in the production of apo-B48 in the blood. This particular mRNA editing mechanism is therefore considered to be beneficial for human health, with potential therapeutic value for lowering blood cholesterol levels. Our understanding of the editing process could result in the development of drugs that either mimic its activity or induce natural apo-B mRNA editing in the human liver. The goal of this research is to define the component proteins that form the editing complex and to understand how they conduct and control successful apo-B mRNA editing. |
Final Report |
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Cigarette smoking is one of the major risk factors for coronary and peripheral vascular disease. Users of tobacco have a 2.5 fold higher prevalence of elevated blood cholesterol than non-smokers. Hypercholesterolemia further increases the risk for cardiovascular disease. Cholesterol is not soluble in the blood and is transported in the blood stream with the help of several proteins. One of these proteins is apolipoprotein B (apo-B), which is found in two different sizes in human blood: the large apo-B 100 and the smaller sized apo-B48. The larger apo-B protein is produced in the liver and the smaller apoB48 is formed in the intestines from a mutated, i.e. edited, form of the mRNA used to produce apoB 100. This editing mechanism is special and is carried out by an enzyme complex called an editing complex. Whenever the apo-B mRNA is present together with this editing complex, the small apo-B48 is produced. Several studies with the focus on levels of cholesterol in the blood discovered that it is preferable to have low amounts of the large apo-B 100. The editing mechanism was therefore considered to lower cholesterol levels. By understanding the editing mechanism it may be possible to develop drugs that either mimic the process or induce apo-B mRNA editing in the liver of man. The goal of this research is to discover the missing proteins that form the editing complex and to understand the mechanism of apo-B mRNA editing. |
