Coagulation is a complex process and there is a delicate balancing act between bleeding disorders and clot formation. Complement activation is known to contribute to thrombotic tissue injury in systemic lupus erythematosus and biomaterial-associated thrombosis, to name a few. Considering the widespread and critical role of thrombosis in many diseases, significant research efforts have been aimed at the discovery and development of safe and effective antithrombotic drugs for acute and chronic purposes. Thus, the purpose of this study is to form a more complete understanding of the role of complement in hemostasis and thrombosis. The long-range goal of our laboratory is to enhance our knowledge of complement-mediated reperfusion injury. The objective of the proposed studies is to understand the molecular mechanisms involved in complement- induced inflammation, coagulation, and thrombogenesis. Preliminary data demonstrates multiple interactions of the MBL complex with several coagulation proteins. This project is particularly novel because, to our knowledge, no studies have investigated the specific role and mechanisms of lectin-mediated coagulation and thrombin-like activity. The underlying rationale of this research is that unearthing the interactions between the complement and coagulation systems may be essential in the development of novel and potentially therapeutic reagents. The role of lectin complexes in thrombogenesis will be examined via the following specific aims: 1) Determine whether lectin complexes have thrombin-like activity in vitro. 2) Determine the contribution of lectin complexes to occlusive thrombosis in vivo. Our laboratory has developed novel in vitro assays for analyzing the mechanisms of complement and coagulation interactions using both human and mouse serum. We possess a vast repertoire of complement deficient mice from which we can gather serum and tissue samples for in vitro studies. In addition, these genetically modified mice allow us to examine individual complement component deficiencies and treatment strategies in a clinically relevant model of vascular occlusion and thrombogenesis in vivo. If successful, results from these studies may indicate a key role for lectin complexes in thrombus formation and coagulopathy, and may lead to the development of improved antithrombotic pharmaceuticals for human clinical applications.
Project Narrative Occlusive thrombosis, resulting from atherosclerotic plaque rupture or restinosis, plays an important role in the onset of two major causes of death in developed nations: myocardial infarction and ischemic stroke. Determining the contribution of complement to thrombogenesis is expected to significantly increase our knowledge regarding hemostasis, vascular occlusion, and thrombolytic therapy. Ultimately, if successful, results obtained in these studies will have a strong clinical and pharmacological impact on the prevention of morbidity and mortality from occlusive thrombosis while simultaneously generating a foundation for future investigations examining the non-immunologic role of complement in human disease.
| Zou, Chenhui; La Bonte, Laura R; Pavlov, Vasile I et al. (2012) Murine hyperglycemic vasculopathy and cardiomyopathy: whole-genome gene expression analysis predicts cellular targets and regulatory networks influenced by mannose binding lectin. Front Immunol 3: |
| La Bonte, Laura R; Pavlov, Vasile I; Tan, Ying S et al. (2012) Mannose-binding lectin-associated serine protease-1 is a significant contributor to coagulation in a murine model of occlusive thrombosis. J Immunol 188:885-91 |
| Pavlov, Vasile I; La Bonte, Laura R; Baldwin, William M et al. (2012) Absence of mannose-binding lectin prevents hyperglycemic cardiovascular complications. Am J Pathol 180:104-12 |
