Microglia, the immune cells of the central nervous system, undertake a number of different functional roles. One major role consists of participating in a signaling pathway that leads to excitatory neuronal death in acute (e.g., stroke), or chronic (e.g., Alzheimer's, amyotrophic lateral sclerosis, glaucoma) neurodegenerative diseases. We propose to investigate the process of microglial activation in this setting of excitotoxic neurodegeneration. Identification and characterization of genes involved in microglial activation could generate potential targets in the CNS for the rational design of new therapeutic approaches for intervention in these diseases. We propose to define, using DNA chip technology, the signaling cascades that result in microglial activation. Furthermore, we will make use of tissue plasminogen activator (tPA), a serine protease that is produced by neurons and microglia and that mediates microglial activation via interaction with a microglial cell surface receptor, annexin II. tPA will be used as a tool to dissect the process of activation, since it functions as an extracellular trigger to activate intracellular effectors. The signaling pathways that lead to microglial activation will be analyzed. This set of experiments will identify candidate targets for subsequent pharmaceutical study for inhibition or suppression of the neurotoxic properties of activated microglia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042168-03
Application #
6853489
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Nunn, Michael
Project Start
2003-01-15
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
3
Fiscal Year
2005
Total Cost
$367,085
Indirect Cost
Name
State University New York Stony Brook
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Miyauchi, Jeremy Tetsuo; Caponegro, Michael D; Chen, Danling et al. (2018) Deletion of Neuropilin 1 from Microglia or Bone Marrow-Derived Macrophages Slows Glioma Progression. Cancer Res 78:685-694
Miyauchi, Jeremy Tetsuo; Tsirka, Stella E (2018) Advances in immunotherapeutic research for glioma therapy. J Neurol 265:741-756
Powell, Jonathan; Mota, Filipa; Steadman, David et al. (2018) Small Molecule Neuropilin-1 Antagonists Combine Antiangiogenic and Antitumor Activity with Immune Modulation through Reduction of Transforming Growth Factor Beta (TGF?) Production in Regulatory T-Cells. J Med Chem 61:4135-4154
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Nissen, Jillian C; Tsirka, Stella E (2016) Tuftsin-driven experimental autoimmune encephalomyelitis recovery requires neuropilin-1. Glia 64:923-36
Torres, Luisa; Danver, Joan; Ji, Kyungmin et al. (2016) Dynamic microglial modulation of spatial learning and social behavior. Brain Behav Immun 55:6-16
Miyauchi, Jeremy T; Chen, Danling; Choi, Matthew et al. (2016) Ablation of Neuropilin 1 from glioma-associated microglia and macrophages slows tumor progression. Oncotarget 7:9801-14
Lewis, Crystal S; Torres, Luisa; Miyauchi, Jeremy T et al. (2016) Absence of Cytotoxicity towards Microglia of Iron Oxide (?-Fe2O3) Nanorhombohedra. Toxicol Res (Camb) 5:836-847
Elmes, Matthew W; Kaczocha, Martin; Berger, William T et al. (2015) Fatty acid-binding proteins (FABPs) are intracellular carriers for ?9-tetrahydrocannabinol (THC) and cannabidiol (CBD). J Biol Chem 290:8711-21

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