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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Small Research Grants (R03)
Project #
1R03NS078392-01
Application #
8283645
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
2012-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$77,000
Indirect Cost
$27,000
Name
University of Connecticut
Department
Neurosciences
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
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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