: Microglia, the immunocompetent cells of the central nervous system, interact with neurons and undertake a number of different functional roles thought to contribute 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 signaling pathways that lead from neuronal insult to microglial activation in a model of excitotoxic neurodegeneration. We propose to characterize the chemotactic gradients that attract microglia to sites of neuronal injury and define the signaling cascades that result in microglial activation. We will make use of tissue plasminogen activator (tPA), a serine protease produced by neurons and microglia that mediates microglial activation via interaction with a microglial cell surface binding partner, annexin A2. We will also analyze the effector pathways that follow tPA / annexin A2-dependent microglial activation and compromise of the blood-brain-barrier. Finally, we will use animals whose microglia are non functional, as well as mice that express EGFP in their microglia and two-photon microscopy to investigate the role of microglia in normal, non-pathological functions in the CNS. outstanding proposal that will investigate the signals the determine whether microglia are neuroprotective or neurotoxic following excitotoxicity. The strengths of the proposal include the productivity of the investigator during the previous funding cycle,. The findings of this study could make a significant contribution to the study of microglia and inflammatory cells in general.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042168-09
Application #
8046314
Study Section
Neural Degenerative Disorders and Glial Biology Study Section (NDGB)
Program Officer
Wong, May
Project Start
2001-07-01
Project End
2013-09-30
Budget Start
2011-04-01
Budget End
2013-09-30
Support Year
9
Fiscal Year
2011
Total Cost
$332,281
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
Nissen, Jillian C; Thompson, Kaitlyn K; West, Brian L et al. (2018) Csf1R inhibition attenuates experimental autoimmune encephalomyelitis and promotes recovery. Exp Neurol 307:24-36
Harrington, Andrea D; Schmidt, Millicent P; Szema, Anthony M et al. (2017) The Role of Iraqi Dust in Inducing Lung Injury in United States Soldiers-An Interdisciplinary Study. Geohealth 1:237-246
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
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
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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