Regulation of Integrin Activation
Initial Award Abstract
Tobacco consumption is an important risk factor for cardiovascular disease. Strokes and myocardial infarctions specifically are strongly linked to cigarette smoking, and approximately 30% of all heart attacks are associated with it. Central to the pathogenesis of cardiovascular disease is the blockage of blood vessels caused by platelet aggregation. Increased platelet aggregation in smokers is indeed well documented. Causal link between tobacco consumption and platelet dysfunction is therefore obvious.
The aggregation of platelets is controlled by proteins called integrins which are expressed on their surface. During wound healing, integrins play a critical role in assisting platelets to form a plug and prevent blood loss. Beta3 integrin is a key type of integrin for platelet aggregation. When damage to blood vessels occurs, chemical signals are released into the blood stream. These chemicals direct platelets to “activate” the beta3 integrins on their surface; an essential process that immediately induces platelet aggregation on the exposed edges of the vessel and that finally leads to blood clot (thrombus) formation. Once a platelet plug is formed, the external bleeding stops. Processes of beta3 integrin activation and platelet aggregation must be tightly controlled because deregulation of such events can result in thrombus formation as in the case of a heart attack. Possible pathological consequences of unregulated integrin activation and the resulting platelet aggregation therefore necessitate a better understanding of the underlying mechanisms.
As beta3 integrin is the main player during platelet aggregation, it has attracted attention as a pharmacological target to prevent thrombus formation, a major cause of cardiovascular events. Although beneficial in some cases, blocking beta3 integrin function presents the undesired side effect of bleeding, limiting the clinical application of such a strategy. A firmer grasp of the fundamental mechanisms regulating beta3 integrin activation is therefore imperative with the premise that such analysis could potentially identify new therapeutic targets.
Our laboratory has demonstrated that beta3 integrin activation requires interaction with another protein called talin. Since the binding of talin to the integrin has been identified as a final step in integrin activation, I propose that integrin activation is controlled by the regulation of the talin binding to integrins. To test this idea, I aim:
1) To identify and characterize an area of talin that is involved in the regulation of the integrin-activating and -binding activities of talin.
2) To investigate the mechanism that keeps talin inactive, i.e. unable to interact with and activate integrins.
3) To reveal a stimulatory event that enables talin to bind to and activate integrins.
The data from the proposed project will surely provide fundamental insights into the mechanism of beta3 integrin activation and may therefore identify novel therapeutic targets for the treatment of tobacco-related diseases. |