The gliotic capsule that forms around a """"""""foreign body"""""""" in the brain is an important, albeit neglected, biological system. Although beneficial overall, the gliotic capsule forms a potentially harmful mass of tissue that contributes to brain swelling and mass effect, and that may shelter foreign cells from surveillance by the immune system. We have found that, in a variety pathological conditions in both rats and humans, reactive astrocytes (R1 astrocytes) in the inner zone of the gliotic capsule express a novel SURl-regulated cation channel, the NCca-ATPchannel, and that this channel directly controls cell viability: opening the channel is associated with necrotic cell death and closing the channel is associated with protection from cell death induced by energy depletion. This discovery can be exploited to allow pharmacological manipulation of R1 astrocytes, leading not only to improved understanding of the basic cellular biology of the gliotic capsule, but also to techniques that will allow manipulation of capsule formation to improve treatment of patients.
In Aim 1 of this proposal, we will expand on preliminary data showing that inhibiting the NCca-ATPchannel protects R1 astrocytes from cell death. We will look at 2 ways to inhibit the channel, with the sulfonylurea, glybenclamide, and with estrogen. In the first part of Aim 1, we will examine in detail the mechanism by which estrogen blocks channel activity, building on preliminary data in which we found that activity of the NCca-ATPchannel in both males and females is inhibited by estrogen via a non-genomic signaling pathway. In the second part of Aim 1, we will use estrogen and glybenclamide to examine the effect of channel inhibition on formation of the gliotic capsule and on development of cerebral edema in vivo.
In Aim 2, we will expand on preliminary data showing that selective killing of R1 astrocytes by diazoxide infusion, which in vitro causes channel opening and necrotic death of R1 astrocytes, results in expansion of the overall astrogliotic response and recruitment of enormous numbers of neutrophils. We will study this response in detail and assess the role of microglia and cytokines in this altered response to injury.
In Aim 3, we will expand on preliminary data showing that expression of the NCca-ATPchannel in vitro requires conditions of hypoxia, and that the inner zone of the gliotic capsule where the channel is found in vivo is hypoxic, suggesting a critical role for hypoxia/HIF1 in channel expression. We will study the role of HIF-1 by inhibiting its expression using antisense oligodeoxynucleotide infusion. Overall, we expect that these studies will build on our recent discovery of the novel SURl-regulated NCca-ATPchannel, and will help to elucidate the function of R1 astrocytes in the inner zone of the gliotic capsule. ? ?
| Simard, J Marc; Geng, Zhihua; Woo, S Kyoon et al. (2009) Glibenclamide reduces inflammation, vasogenic edema, and caspase-3 activation after subarachnoid hemorrhage. J Cereb Blood Flow Metab 29:317-30 |
| Gerzanich, Volodymyr; Woo, S Kyoon; Vennekens, Rudi et al. (2009) De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury. Nat Med 15:185-91 |
| Simard, J Marc; Yurovsky, Vladimir; Tsymbalyuk, Natalia et al. (2009) Protective effect of delayed treatment with low-dose glibenclamide in three models of ischemic stroke. Stroke 40:604-9 |
| Simard, J Marc; Woo, S Kyoon; Bhatta, Sergei et al. (2008) Drugs acting on SUR1 to treat CNS ischemia and trauma. Curr Opin Pharmacol 8:42-9 |
| Simard, J Marc; Castellani, Rudolph J; Ivanova, Svetlana et al. (2008) Sulfonylurea receptor 1 in the germinal matrix of premature infants. Pediatr Res 64:648-52 |
| Simard, J Marc; Tarasov, Kirill V; Gerzanich, Volodymyr (2007) Non-selective cation channels, transient receptor potential channels and ischemic stroke. Biochim Biophys Acta 1772:947-57 |
| Simard, J Marc; Kent, Thomas A; Chen, Mingkui et al. (2007) Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol 6:258-68 |
| Liang, Danny; Bhatta, Sergei; Gerzanich, Volodymyr et al. (2007) Cytotoxic edema: mechanisms of pathological cell swelling. Neurosurg Focus 22:E2 |
| Kunte, Hagen; Schmidt, Sein; Eliasziw, Michael et al. (2007) Sulfonylureas improve outcome in patients with type 2 diabetes and acute ischemic stroke. Stroke 38:2526-30 |
| Simard, J Marc; Tsymbalyuk, Orest; Ivanov, Alexander et al. (2007) Endothelial sulfonylurea receptor 1-regulated NC Ca-ATP channels mediate progressive hemorrhagic necrosis following spinal cord injury. J Clin Invest 117:2105-13 |
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