Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a pleiotrophic extracellular protein that is dramatically upregulated in the brain following inflammation or injury. TIMP-1 has a well described function as an endogenous regulator of the proteolytic activities of the matrix metalloproteinases (MMPs) a family of extracellular enzymes that play critical roles in cellular homeostasis, adaptation and tissue remodeling. TIMP-1 also has noted MMP-independent functions including antiapoptotic activity and trophic actions. These latter functions of TIMP-1 have been implicated in synaptic plasticity, neuroprotection, oncogenesis and oligodendrocyte differentiation. TIMP-1 can be expressed by a variety of cell types in the CNS: astrocytes robustly express TIMP-1 in response to inflammatory demyelination or bacterial infection in the CNS, and neurons have been reported to express TIMP-1 following excitotoxic injury. In the course of CNS injury and inflammation, it is also important to point out that TIMP-1 is also expressed by immune cells, including T cells, macrophages and microglia. Thus, TIMP-1 can be rapidly expressed by a variety of cell types offering a myriad of potential roles for TIMP-1 in response to CNS injury or disease. Currently, only global TIMP-1KO mice are available for study meaning that the cellular source of TIMP-1 remains a confounding variable to our understanding on the specific mechanistic roles of TIMP-1 in the brain. To test whether production of TIMP-1 from specific cell types differentially impact neuropathology, we will develop an essential new reagent: a conditional TIMP-1 knockout mouse (TIMP-1cKO) line. This mouse line will significantly advance our understanding of TIMP-1 and its functions in the CNS by enabling us to directly test whether cell specific-TIMP-1 expression impacts the innate potential for brain recovery following injury.
The first aim of this proposal will be to develop the new TIMP-1cKO mouse, which will then be crossed with the GFAP-Cre transgenic mouse to specifically knockout TIMP-1 expression from astrocytes throughout the CNS. Astrocyte-specific TIMP-1cKO mice will then be tested and compared with global Together this work will, (a) provide a valuable new reagent for advanced study on TIMP-1 in a wide variety of disease models, including neurological diseases, and, (b) experimental results from this work will validate the TIMP-1cKO mouse as a viable new mouse line for study of cell-specific deletion of TIMP-1.

Public Health Relevance

Tissue inhibitor of metalloproteinase-1 (TIMP-1) is a protein that can protect the brain from injury and disease in a variety of ways. The purpose of this research project is to develop a new mouse strain where this protein can be eliminated from specific cells, and in so doing allow us to better understand how TIMP-1 can influence the behaviour of different types of cells during disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Research Grants (R03)
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Cellular and Molecular Biology of Glia Study Section (CMBG)
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Morris, Jill A
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University of Connecticut
Schools of Medicine
United States
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Claycomb, Kumiko I; Winokur, Paige N; Johnson, Kasey M et al. (2014) Aberrant production of tenascin-C in globoid cell leukodystrophy alters psychosine-induced microglial functions. J Neuropathol Exp Neurol 73:964-74
Claycomb, Kumiko I; Johnson, Kasey M; Bongarzone, Ernesto R et al. (2014) An in vitro model for the study of cellular pathophysiology in globoid cell leukodystrophy. J Vis Exp :e51903