The applicant seeks to become a superb clinician-scientist. After graduating summa cum laude from college and medical school, he trained in surgery at the Massachusetts General Hospital. He undertook a 2-yr research fellowship at the NIH, and despite having substantial clinical duties, he has continued high-quality basic research over the last 4 1/2 years at the University of Pittsburgh. To develop his research career, he seeks more time commitment to basic research, something that would be made possible by the K08 award. The research environment provided by the surgery department is unsurpassed, offering opportunities to learn and use advanced research techniques. The lab here has a distinguished history of NIH grants and it has trained several successful surgeon-scientists. This proposal stems from the applicant's broad goal of understanding the problem of thrombosis. Although the etiology of thrombosis is multifactorial, one molecule that is of undisputed importance is tissue factor (TF). We offer the novel hypothesis that nitric oxide (NO) is an important regulator of TF. There are good reasons to examine NO as a TF regulator. NO has diverse effects and there is significant overlap between the signaling systems affected by NO and those known to affect TF. A primary target for both is the vascular system. TF reduction by NO would be consistent with NO's vascular homeostasis function. However, when induced in large amounts, NO is deleterious in many biologic settings. TF is a cause of organ damage in many of these same settings. Preliminary work suggests that NO upregulates TF in vascular smooth muscle cells (SMC) and endothelial cells (EC). Also, we have found that NO may be needed for the TF upregulation normally seen during reperfusion after ischemia. We hypothesize that NO upregulates TF, and that this upregulation is biologically relevant.
Aim 1 : To determine the mechanisms by which NO enhances TF expression in vascular SMC and EC. We will study EC and SMC in cell and organ culture to accomplish this aim.
Aim 2 : To determine the significance of NO regulation of TF in reperfusion after shock and ischemia. We will study TF regulation by NO, using mice deficient in inducible nitric oxide synthase, the enzyme that synthesizes induced NO.
Aim 3 : To determine the significance of NO regulation of TF in atherosclerotic plaques. We will study transgenic mice prone to develop atherosclerosis, so we can determine whether NO-regulates TF in atheromas.
| Kibbe, Melina R; Johnnides, Christopher; Gleixner, Susan et al. (2003) Regulation of tissue factor expression in smooth muscle cells with nitric oxide. J Vasc Surg 37:650-9 |
