Grant: Project Grant

While there have been recent major gains in treating obesity and type 2 diabetes, these medical disorders remain common and are complicated, particularly by an increased risk of heart disease, stroke, and excess blood clotting (thrombosis). The reason for this association is not clearly understood. However such knowledge is important to gain, as it would allow the development of novel strategies to prevent the complications. Working in both the fields of blood clotting and diabetes, our studies show that the key molecules involved in these disorders, i.e., so-called "tissue factor" for blood clotting and the "insulin receptor" for diabetes and obesity, interact with each other. Indeed, in convincing preliminary experiments, we show that tissue factor makes diabetes worse, while the insulin receptor reduces blood clotting. Thus, it appears that they control each other. In this research program, we propose to investigate how these 2 proteins cooperate. We will use many techniques, including 1. growing the relevant fat cells and blood vessel cells in culture systems, 2. using protein chemistry and microscopy techniques to examine affected tissues and cells, 3. performing studies with genetically modified mice that lack one or more of these proteins and treating them with agents that affect blood clotting and/or diabetes, and 4. using sophisticated methods to examine the 3-D structure of the proteins when apart and together, thereby determining precisely where they interact and how one might interfere with the interactions. Overall, our work will result in new information as to how type 2 diabetes, obesity and excess blood clotting are linked. This will hopefully lead to insights toward the design of new preventative and therapeutic strategies for these common medical problems.