Disturbance of Ca2+ homeostasis is a major cause of neuronal injury in transient ischemia and several neurodegenerative disorders such as Alzheimer's disease (AD), polyglutamine diseases, and Parkinson's disease. The endoplasmic reticulum (ER) is a major organelle for Ca2+ storage. The ER regulates multiple cellular functions through Ca2+ signaling, and provides a specialized environment for post-translational folding and maturation of transmembrane and luminal proteins. Loss of Ca2+ from intracellular stores causes elevation of cytosolic Ca2+, which can lead to neuronal vulnerability resulting from activation of intrinsic cell death pathways. In addition, since protein chaperones use Ca2+ as a cofactor, release of ER Ca2+ also causes cell injury through an accumulation of misfolded proteins. Physiological, pathological and experimental conditions that perturb ER function cause accumulation of misfolded proteins within the ER, and as a result of the ensuing ER stress, activate compensatory signaling pathways collectively known as the unfolded protein response (UPR). In this proposal we outline our strategy to develop a mouse model for neuroprotection against Ca2+ deregulation, based on overexpression of stanniocalcin 2 (STC2). We recently identified STC2 as a gene induced by the mammalian UPR, hypoxia, and cerebral ischemia. We further demonstrated that in cultured cells expression of STC2 is essential and sufficient to offer cytoprotection against cell death induced by disruption of ER Ca2+ homeostasis. STC2 is a secreted glycoprotein hormone highly conserved in fish and mammals. We postulate that STC2 carries out a distinct function in mammals as a critical survival component of the UPR, defending cells from injury caused by disruption of Ca2+ homeostasis under pathological conditions. The following are the specific aims of this proposal:
Aim 1. To generate transgenic mice with spatial/temporal control of STC2 expression.
Aim 2. To characterize the neuroprotective function of STC2. Our investigation will develop a valuable resource for the scientific community - transgenic mice with spatial and temporal control of STC2 expression, and perform in vitro and in vivo feasibility studies that will provide the proof of principle to demonstrate neuroprotective properties of STC2 against cell death initiated by deregulation of Ca2+ homeostasis. Outcome of our investigation will be critical for the future development of STC2 based therapeutic strategy to prevent neuronal death. ? ?
| Zeiger, William; Ito, Daisuke; Swetlik, Carol et al. (2011) Stanniocalcin 2 is a negative modulator of store-operated calcium entry. Mol Cell Biol 31:3710-22 |
