Microglia cells are the major fully immunocompetent cells of the brain, where they serve similar functions as macrophages in peripheral tissues. It is becoming apparent that most chronic neurodegenerative diseases, such as Alzheimer's, and even acute events such as trauma and stroke have strong immunological components involving microglia cells. Other immunocompetent cells use calcium signaling as central mechanism for numerous cellular functions, including proliferation. However, the involvement of calcium and the role of different calcium signaling mechanisms in microglia activation is largely unknown. Indicated in the literature and supported by our experimental observations, we hypothesize that calcium mobilization plays a pivotal role in microglia activation. We therefore propose experiments that will: 1) Identify criteria do discern activated microglia, evaluating ion channel expression levels, cytokine production, morphological changes and immunocytochemistry; 2) Explore the dependence of microglia activation on the magnitude, duration and temporal patterns of calcium signals; 3) Investigate the role of CRAC channels in microglia activation; 4) Assess the role of ATP-gated channels in microglia activation; 5) Assess the relative roles and efficacies of CRAC and ATP-gated channels in activating microglia; 6) Identify physiological and pathological microglia activators involving calcium signaling and 7) Investigate the cross-talk of calcium signaling mechanisms initiated by various microglia activators. The laboratory's approach to study these questions is at the single-cell level and employs a combination of biophysical techniques (patch-clamp electrophysiology, video microscopy, and dual-wavelength fluorometry). We will assess physiological parameters such as ionic fluxes, membrane potential, and intracellular calcium levels. These techniques are complemented by immunofluorescence and pharmacological tools to investigate calcium signaling in microglia cells. Answers to the questions above will enlighten the understanding of the calcium signaling events in microglia cells and may yield information to identify future targets for therapeutic intervention in the serious CNS pathologies that are attributable to microglia activation.

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-4 (01))
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Behar, Toby
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Queen's Medical Center
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Beck, Andreas; Penner, Reinhold; Fleig, Andrea (2008) Lipopolysaccharide-induced down-regulation of Ca2+ release-activated Ca2+ currents (I CRAC) but not Ca2+-activated TRPM4-like currents (I CAN) in cultured mouse microglial cells. J Physiol 586:427-39
Parvez, Suhel; Beck, Andreas; Peinelt, Christine et al. (2008) STIM2 protein mediates distinct store-dependent and store-independent modes of CRAC channel activation. FASEB J 22:752-61
Cheng, Henrique; Beck, Andreas; Launay, Pierre et al. (2007) TRPM4 controls insulin secretion in pancreatic beta-cells. Cell Calcium 41:51-61
Tani, Dawn; Monteilh-Zoller, Mahealani K; Fleig, Andrea et al. (2007) Cell cycle-dependent regulation of store-operated I(CRAC) and Mg2+-nucleotide-regulated MagNuM (TRPM7) currents. Cell Calcium 41:249-60
Penner, R; Fleig, A (2007) The Mg2+ and Mg(2+)-nucleotide-regulated channel-kinase TRPM7. Handb Exp Pharmacol :313-28
Demeuse, Philippe; Penner, Reinhold; Fleig, Andrea (2006) TRPM7 channel is regulated by magnesium nucleotides via its kinase domain. J Gen Physiol 127:421-34
Peinelt, Christine; Vig, Monika; Koomoa, Dana L et al. (2006) Amplification of CRAC current by STIM1 and CRACM1 (Orai1). Nat Cell Biol 8:771-3
Vig, M; Peinelt, C; Beck, A et al. (2006) CRACM1 is a plasma membrane protein essential for store-operated Ca2+ entry. Science 312:1220-3
Beck, Andreas; Kolisek, Martin; Bagley, Leigh Anne et al. (2006) Nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose regulate TRPM2 channels in T lymphocytes. FASEB J 20:962-4
Kolisek, Martin; Beck, Andreas; Fleig, Andrea et al. (2005) Cyclic ADP-ribose and hydrogen peroxide synergize with ADP-ribose in the activation of TRPM2 channels. Mol Cell 18:61-9

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