Proteolysis of brain extracellular matrix (ECM) increases capillary permeability and produces brain edema. This proposal is to understand the molecular events involved in blood-brain barrier (BBB) proteolysis. BACKGROUND: Bacterial collagenase causes hemorrhagic necrosis in brain. 72-kDa type W collagenase opens the BBB by disrupting the capillary basal lamina. 92-kDa type W collagenase is secreted during brain injury. Tumor necrosis factor-alpha and interleukin-1beta induce expression of 92-kDa gelatinase. Preliminary studies of CSF from patients.with inflammatory and infectious diseases show expression of 92-kDa type IV collagenase.
SPECIFIC AIMS :
The aims are: 1) to determine the effect of endopeptidases on brain ECM and BBB; 2) to measure the effect of cytokines on matrix metalloproteinase production and BBB permeability; and 3) to test agents that could reduce proteolytic damage and vasogenic edema. EXPERIMENTS: Adult rats are injected intracerebrally with heparinase, elastase, plasmin, and cathepsin D; histological studies are done and BBB permeability is measured. Other groups of rats are injected intracerebrally with tumor necrosis factor-alpha and interleukin-1beta; BBB permeability is measured by radioisotopes, and matrix metalloproteinase expression is assayed by zymography and confirmed by Western blots, using monoclonal antibodies. Finally, the effect of glucocorticoids and transforming growth factor-fl on expression of metalloproteinases and capillary permeability will be tested. SIGNIFICANCE: Endopeptidases may link cytokines to capillary damage and vasogenic edema in a number of common neurological conditions. Agents that block brain ECM proteolysis may provide novel treatments for brain injury.
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