Matrix metalloproteinases (MMPs) disrupt the blood-brain barrier (BBB) in many neuroinflammatory diseases. They are secreted as latent enzymes, which are activated by proteases and free radicals and inhibited by tissue inhibitors of metalloproteinases (TIMPs). Gelatinase A (MMP-2) and B (MMP-9) attack extracellular matrix around blood vessels. Cell cultures of astrocytes produce latent MMP-9 when stimulated by lipopolysaccharide (LPS), and microglia form active MMP-9. Microglia secrete stromelysin- 1 (MMP-3), which may be the activator of MMP-9. Intracerebral injection of LPS induces cytokines, free radicals, and proteases that simulate the neuroinflammatory response by producing active forms of the MMPs and opening the BBB. We hypothesize that the balance between the MMPs and the TIMPs controls the permeability of the BBB, and that MMP-3 contributes to the BBB damage by activation of proMMP-9, while TIMP-3 protects the BBB by inhibiting the MMPs. To test the hypothesis, we propose to use mice lacking the MMP-3 or TIMP-3 genes.
Specific Aim 1 : To determine the relationship of the expression of the cytokines, MMPs, and TIMPs to the BBB damage after an intracerebral injection of LPS in mice. 3H-sucrose (m.w. 342) and 14C-dextran (m.w. 50-90 kDa) will be used for BBB permeability measurements. Expression of mRNA for TNF-alpha, IL-1beta, MMP-2, -3, and -9, and TIMP-1 and -3 will be measured by realtime rtPCR. Zymography and immunohistochemistry of the MMPs and TIMPs will be used to determine proteins and cellular localization.
Specific Aims 2 and 3: To study the role of MMP-3 (aim 2) and TIMP-3 (aim 3) in BBB proteolysis by the use of MMP-3 and TIMP-3 null mice. BBB permeability will be measured with radiolabeled tracers, and the effect of gene knock out on the production and activation of the MMPs will be measured by zymography and rt-PCR.
Specific Aim 4 : To identify the molecular mechanisms involved in the protection of the BBB by corticosteroids, tetracycline derivatives, and synthetic MMP inhibitors. BBB disruption is a major factor in multiple sclerosis, Guillain-Barre Syndrome, meningitis, and cerebral bleeding after thrombolysis. Understanding the molecular events in the BBB disruption by MMPs will provide a rational basis for drug design, and will lead to novel treatments in many important neurological diseases.
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