Microglial cells are the resident immune cells of the central nervous system (CNS). They have been implicated in many acute and chronic neurological diseases, including trauma, stroke and multiple sclerosis. Upon CNS injury microglial cells are rapidly activated. Through the release of bioactive substances such as cytokines activated microglial cells can exert powerful toxic as well as protective effects on neurons. Until recently, research has mainly focused on microglial activation by cytokines. These potent peptides elicit a broad range of responses, including proliferation, motility and cytokine release itself. Nevertheless, before cytokines can activate microglia, they need to be induced, synthesized and released from neighboring cells. The reported rapid activation of microglia after CNS injury, leads to the question: Are there other, factors acting as microglial activators? One group of candidates is serum factors (SFs). SFs leak into the CNS parenchyma during insults associated with impairment of the blood-brain-barrier, such as trauma, stroke, and multiple sclerosis. Serum factors therefore could serve as immediate signals of injury and activate microglial cells without the need of intermediary, cytokine- producing """"""""relay"""""""" cells. We hypothesize that serum factors (SF) represent a """"""""short-cut"""""""" to microglial activation. Based on recently published reports and our preliminary findings, we propose to examine the effects of the serum factors thrombin, lysophosphatidic acid and sphingosine-1 -phospate on microglial Activation. Using molecular, immunological and imaging techniques the following issues will be addressed: 1. Determine the cellular consequences of microglial activation by SFs in vitro. 2. Determine the signal transduction mechanisms involved in SF-mediated microglial activation in vitro. 3. Determine the cellular consequences of microglial activation by SFs in a retina explant culture model in situ. In many pathological events SFs act immediately on microglial cells, long before first-phase cytokines could influence microglial behavior. Each of the receptors or signal transduction mechanisms identified may constitute a new target for therapeutic intervention in CNS injuries, which are accompanied by the break down of the blood-brain-barrier, such as trauma, multiple sclerosis or stroke.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS044337-02
Application #
6637739
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Nunn, Michael
Project Start
2002-07-01
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
2
Fiscal Year
2003
Total Cost
$324,045
Indirect Cost
Name
University of Washington
Department
Neurology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Weinstein, Jonathan R; Zhang, Matthew; Kutlubaev, Mansur et al. (2009) Thrombin-induced regulation of CD95(Fas) expression in the N9 microglial cell line: evidence for involvement of proteinase-activated receptor(1) and extracellular signal-regulated kinase 1/2. Neurochem Res 34:445-52
Weinstein, Jonathan R; Swarts, Sarah; Bishop, Caroline et al. (2008) Lipopolysaccharide is a frequent and significant contaminant in microglia-activating factors. Glia 56:16-26
Weinstein, Jonathan R; Ettinger, Russell E; Zhang, Matthew et al. (2008) Thrombin regulates CD40 expression in microglial cells. Neuroreport 19:757-60
Moller, Thomas; Weinstein, Jonathan R; Hanisch, Uwe-Karsten (2006) Activation of microglial cells by thrombin: past, present, and future. Semin Thromb Hemost 32 Suppl 1:69-76
Garden, Gwenn A; Moller, Thomas (2006) Microglia biology in health and disease. J Neuroimmune Pharmacol 1:127-37
Weinstein, Jonathan R; Hong, Soyon; Kulman, John D et al. (2005) Unraveling thrombin's true microglia-activating potential: markedly disparate profiles of pharmaceutical-grade and commercial-grade thrombin preparations. J Neurochem 95:1177-87
Balcaitis, Stephanie; Weinstein, Jonathan R; Li, Sheng et al. (2005) Lentiviral transduction of microglial cells. Glia 50:48-55
Garden, Gwenn A; Guo, Weiqun; Jayadev, Suman et al. (2004) HIV associated neurodegeneration requires p53 in neurons and microglia. FASEB J 18:1141-3
Witting, Anke; Walter, Lisa; Wacker, Jennifer et al. (2004) P2X7 receptors control 2-arachidonoylglycerol production by microglial cells. Proc Natl Acad Sci U S A 101:3214-9
Walter, Lisa; Dinh, Thien; Stella, Nephi (2004) ATP induces a rapid and pronounced increase in 2-arachidonoylglycerol production by astrocytes, a response limited by monoacylglycerol lipase. J Neurosci 24:8068-74

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