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Role of caveosome-medicated endocytosis during MMP-2 activation

Objective

The turnover and remodelling of extra cellular matrix (ECM) is an important feature after vascular injury in noontime formation and remodelling of the injured vessels. Collagen is the major ECM protein and can only be degraded by the matrix metalloproteases (Mumps). Broad spectrum MMP-inhibitors can prevent arterial shrinkage and noontime formation but suffer from severe side effects after prolonged administration in humans. To find a specific target(s) for intervention, we have to understand how turnover of collagen is regulated. Collagen degradation is dependent on the action of several matrix metalloproteinases and MMP activity is regulated at multiple levels. The expression ofMT1-MMP, MMP2 and MMP-9 are early unregulated in time after vascular injury. Although, the activation of MT-1MMP(MMP2) takes place on the cell surface the compartmental basis for integrating the Tran membrane signalling underlying the MMP2 activation cascade into cells remains to be established. MMP2, MT1-MMP and TIMP-2 are co-localized with Caveolin-1, a major constituent of theCaveolae. The cellular functions of Cavalla are not yet fully understood. Recently, the study of sub cellular distribution of carboxyl-terminally green fluorescent protein GFP-tagged Cav-1 (Cav-1-GFP) revealed that this protein has high mobility within cells. Cav-1 can be found at the cell surface, associated with Googly complex and present in alveolar vesicles.
Cav-1,moves bi-directional between the cell surface and cell interior. Several reports have shown that certain viruses, lipid-bound toxins and certain glycosylphosphosphatidylinositol (GPI)- linked proteins enter cells and are sorted to different sub cellular locations bypassing endoscopes using a recently described organelle (termed the \"Cave some\"). This organelle has been visualized by electronic microscopy and it lacks markers for early-endoscopes, liposome’s, ER or Googly complex but are rich in caveolin-1.

Call for proposal

FP6-2002-MOBILITY-5
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Coordinator

UNIVERSITY MEDICAL CENTER UTRECHT. HEART LUNG CENTER UTRECHT
Address
Heidelberglaan 100, Room G02-523
Utrecht
Netherlands