In a number of neurodegenerative, microglia/macrophages have been found associated within the neural lesions. Thus, it is postulated that microglia/macrophages may exacerbate neurodegenerative diseases. A receptor tyrosine kinase, Mer, expressed on macrophage, has recently been shown involved in signal transduction and downregulation of the immune response. Mer functional mutant (Mer kd) mice wer generated by deletion of a tyrosine kinase domain in the cytoplasmic tail by gene targeting. Mer mice upon LPS challenge showed greater mortality, elevated in the levels of TNF-alpha, increase NF- kB nuclear translocation, and decreased apoptosis as compared to wildtype mice. Hence, Mer is involved in a signal transduction pathway that can attenuate macrophages through the regulation of pro-inflammatory cytokines and programmed cell death. In this proposal, the role of Mer in CNS demyelination will be investigated. In a functional knockout mouse, using a genetic and neurotoxin-induced model of demyelination, the role of Mer will be assessed . Secondly, the effect of Mer on signally TNF-alpha production in macrophages and in DCNS demyelination will be elucidate in vivo and in vitro. Finally, a Mer transgenic mouse will be generated to analyze the impact of Mer overexpression on microglia/macrophage activation and CNS demyelination. These experiments will elucidate the role of microglia/macrophages in CNS demyelination and provide a molecular target that can be used in the development of therapies for neurodegenerative and demyelination diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
3F32NS010799-01S1
Application #
6082369
Study Section
Special Emphasis Panel (ZRG1 (02))
Program Officer
Kerza-Kwiatecki, a P
Project Start
1999-03-01
Project End
Budget Start
1998-09-21
Budget End
1999-09-20
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599