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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-MDCN-2 (01))
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Behar, Toby
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University of Washington
Schools of Medicine
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