Traumatic brain injury initiates a sequence which includes both beneficial and detrimental events. Injury to the cerebral cortex results in rapid degeneration of thalamic neurons which are not available for reconnection to undamaged cortex. Microglia are key cells in the response to brain injury. Monocyte-chemoattractant-protein-1 undamaged cortex. Microglia are key cells in the response to brain injury. Monocyte-chemoattractant-protein-1 (MCP-1) is a chemokine expressed following injury which attracts microglia and other cells of the monocyte lineage. Preliminary experiments have identified rapid expression of MCP-1 in the thalamus following cortical lesions. The hypothesis is that MCP-1 is the critical molecule in modulation brain repair responses. In this proposal, induced mutants/genetic models of brain-targeted MCP-1 over-expression, knockout of MCP-1, and knockout of the high affinity MCP-1 receptor (CCR2), will provide in vivo modulation of MCP-1. The proposed experiments will examine the extend and temporal pattern of axotomized neuron death and of microglial migration, activation and proliferation in the thalamus. The following specific aims are proposed 1) To determine the effect of brain-targeted over- expression of MCP-1 on degeneration of thalamic neurons following cortical injury, 3) to determine the effect of ablation of MCP-1 and of its high affinity receptor, CCR-2, on degeneration of thalamic neurons following cortical injury, 4) to determine the effect of genetic manipulation of MCP-1 and its receptor n monocyte trafficking and microglial migration following cortical lesions. Understanding the role of MCP-1 in attracting of monocytes and microglial to sites of damage, and in activation of these cells, may lead to determination of targets for therapies for treatment for brain injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038282-03
Application #
6394062
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Michel, Mary E
Project Start
1999-07-01
Project End
2003-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
3
Fiscal Year
2001
Total Cost
$218,028
Indirect Cost
Name
University of Kansas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Liverman, Christopher S; Cui, Lisa; Yong, Chi et al. (2004) Response of the brain to oligemia: gene expression, c-Fos, and Nrf2 localization. Brain Res Mol Brain Res 126:57-66
Sandhir, Rajat; Puri, Veena; Klein, Robert M et al. (2004) Differential expression of cytokines and chemokines during secondary neuron death following brain injury in old and young mice. Neurosci Lett 369:28-32
Choudhuri, Rajani; Cui, Lisa; Yong, Chi et al. (2002) Cortical spreading depression and gene regulation: relevance to migraine. Ann Neurol 51:499-506
Muessel, Michelle J; Klein, Robert M; Wilson, Angela M et al. (2002) Ablation of the chemokine monocyte chemoattractant protein-1 delays retrograde neuronal degeneration, attenuates microglial activation, and alters expression of cell death molecules. Brain Res Mol Brain Res 103:12-27
Muessel, M J; Berman, N E; Klein, R M (2000) Early and specific expression of monocyte chemoattractant protein-1 in the thalamus induced by cortical injury. Brain Res 870:211-21