The long-term objective of this research program is to advance the current knowledge of blood-brain barrier disruption in the setting of tumor-associated brain edema. This will be accomplished by studying a vascular permeability factor (VPF), that is expressed by malignant glial tumors grown in tissue culture. In addition to promoting microvascular permeability, partially purified VPF is known to induce transient changes in endothelial cytosolic calcium. Of particular interest is how the VPF-induced intracellular calcium ion flux, alterations in the F-actin content, and changes in endothelial cytoarchitecture, may relate to impaired blood-brain barrier integrity in the setting of intracerebral tumor. Furthermore, the mechanism of glucocorticosteroid-induced inhibition of VPF activity, and its relevance to the known clinical efficacy of dexamethasone in the setting of neoplastic brain edema will be studied. This research seeks to supplement the current understanding of neoplastic blood-brain barrier disruption in hopes of proposing novel and more effective therapeutic alternatives. Specifically, to test the hypothesis that: VPF plays an integral role in the genesis of neoplastic brain edema. The following specific aims have been devised to support or test this hypothesis. To determine if: (1) VPF is capable of inducing cytosolic calcium changes in cultured brain and retinal endothelial cells, (2) VPF is capable of altering the cytoarchitecture of brain and retinal endothelial cells grown in monolayer cultures, (3) VPF is capable of altering the physiological barrier integrity of brain and retinal endothelial cells grown in monolayer cultures, (4) VPF activity may be inhibited in vitro and in vivo is; and to propose that effective inhibitory agents (VPF antagonists) may be applicable to the treatment of tumor-induced vasogenic brain edema. The methodology will include standard tissue culture techniques, use of a biological assay for quantifying VPF induced microvascular permeability, determination of endothelial cytosolic calcium changes in response to VPF exposure using a fluorescent intracellular calcium ion probe (fura-2/AM), monitoring endothelial cells for evidence of VPF-induced cytoarchitectural changes. by assaying for F-actin and by using electron microscopy, and using radiolabeled albumin to study the barrier integrity of endothelial cells grown in monolayers. The health-relatedness of this project derives from the substantial morbidity associated with peritumoral brain edema. Improvements in therapeutic intervention will result from a more complete understanding of this process. Ultimately, effective treatment of neoplastic brain edema will reduce the risk of surgically-induced neurological deficits, and improve patient tolerance of adjunctive radiotherapy, chemotherapy, and immunotherapy.

National Institute of Health (NIH)
National Cancer Institute (NCI)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Pathology A Study Section (PTHA)
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Yale University
Schools of Medicine
New Haven
United States
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