Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) is an inhibitor of the 16 matrix metalloproteinases (MMPs) that collectively degrade all extracellular matrix. Mice deficient for TIMP-1 were shown to be hyper-resistant to P. aeruginosa corneal infections by a complement-dependent mechanisms. Long infections were also cleared more effectively and inflammatory responses to three additional stimuli were altered in mutant mice. Furthermore, differences in vascular structure and/or function were observed in mutant animals using four different assays. Vascular changes may underlie the altered responses to infection and inflammation in TIMP- 1-deficient mice. The goal of this proposal is to elucidate the mechanisms underlying the altered response to infection and inflammation in timp-1 mutants. The first two Aims seek to determine which of the two mechanisms used by complement to kill bacteria is required for the phenotype and if complement activity itself is affected by the timp-1 mutation.
The third Aim i s designed to determine whether TIMP-1 phenotype, and identify the structural changes in the vasculature that have occurred.
The fourth Aim seeks to determine if TIMP-1 loss alters sensitivity to ocular inflammation and breakdown of the blood aqueous or blood retinal barriers. Evidence id described demonstrating that the effect of TIMP-1 loss on hyper-resistance to corneal infection is indirect, mediated by one or more MMPs.
Aim 5 is designed to identify the key MMP(s) responsible for the mutant phenotype. The fact that hyper-resistance to pulmonary infections is seen in timp-1 mutants may be enormous clinical significance to immunocompromised individuals, or people with cystic fibrosis or pneumonia. Each of these groups is at risk of life-threatening pulmonary infections. If loss of TIMP-1 facilitates more effective clearance of such infections, perhaps interfering with TIMP-1 function would be of great benefit to these people. A simple genetic experiment proposed in Aim 6 will confirm if this is the case. Im 7 propose to use phage display to identify TIMP-1 antagonists that may have a wide variety of therapeutic uses.
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