This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The utilization of hematopoietic cell transplants (HCT) for treatment of malignant and non-malignant disorders is widespread with over 17,000 allogeneic transplants performed yearly. HCT involves the use of high dose chemotherapy and/or total body irradiation (TBI) as part of the conditioning regimen. Despite improved overall survival and decreased morbidity, severe life-threatening complications remain from this intensive treatment modality. These complications include: Graft versus Host Disease (GVHD), hepatic veno-occlusive disease (VOD), pulmonary hemorrhage, capillary leak syndrome (CLS), idiopathic pneumonia syndrome (IPS), multiple organ dysfunction syndrome (MODS), hemorrhagic cystitis, other bleeding and thrombotic events and death. In addition, undergoing HCT can put patients at increased risk for early cardiovascular disease. Currently no reliable method exists to determine which patients are most at risk for these complications. The pathophysiology of each of these disorders, though, is in part related to vascular injury and endothelial dysfunction. Biomarkers of endothelial injury may therefore correlate with the incidence and severity of these complications. However, studies that directly measure vascular function after exposure to high dose chemotherapy and/or TBI have not been done. This proposal will utilize our unique capabilities to be able to measure vascular endothelial function in order to determine the acute changes evident immediately after exposure to high dose chemotherapy and TBI and to determine whether these changes persist over time. An improved understanding of the acute effects of the intensive HCT conditioning regimen of high dose chemotherapy and TBI on endothelial function will help identify patients at risk for early-onset complications as well as those at risk for long-term cardiovascular complications and may provide opportunities for preventative therapy.
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