Mouse model for neuroprotection

神经保护小鼠模型

• 批准号: 7019332
• 负责人: GOPAL THINAKARAN
• 金额: $ 17.23万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7019332
• 关键词: calcium flux; calcium ion; calcium metabolism; cerebral ischemia /hypoxia; cytoprotection; endoplasmic reticulum; genetically modified animals; glycoproteins; homeostasis; hormone regulation /control mechanism; hypercalcemia; laboratory mouse; neuroprotectants; tetracyclines; tissue /cell culture

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：Ca 2+稳态紊乱是短暂性缺血和几种神经退行性疾病（如阿尔茨海默病（AD）、多聚谷氨酰胺病和帕金森病）中神经元损伤的主要原因。内质网（ER）是储存Ca ~（2+）的主要细胞器。ER通过Ca 2+信号调节多种细胞功能，并为跨膜和管腔蛋白的翻译后折叠和成熟提供专门的环境。从细胞内储存的Ca 2+的损失引起胞质Ca 2+的升高，这可导致由内在细胞死亡途径的激活引起的神经元脆弱性。此外，由于蛋白伴侣使用Ca 2+作为辅因子，ER Ca 2+的释放也通过错误折叠蛋白的积累引起细胞损伤。干扰ER功能的生理、病理和实验条件导致错误折叠蛋白在ER内积累，并且作为随后的ER应激的结果，激活补偿信号通路，统称为未折叠蛋白反应（UPR）。在这个建议中，我们概述了我们的策略，开发一个小鼠模型的神经保护钙失调，基于斯钙素2（STC 2）的过表达。我们最近发现STC 2是一个由哺乳动物UPR、缺氧和脑缺血诱导的基因。我们进一步证明，在培养的细胞中，STC 2的表达是必不可少的，足以提供细胞保护，防止细胞死亡诱导的ER Ca 2+稳态的破坏。STC 2是一种在鱼类和哺乳动物中高度保守的分泌型糖蛋白激素。我们推测，STC 2在哺乳动物中作为UPR的关键存活组分执行独特的功能，在病理条件下保护细胞免受由Ca 2+稳态破坏引起的损伤。本提案的具体目标如下：目标1。产生具有STC 2表达的空间/时间控制的转基因小鼠。目标2.为了表征STC 2的神经保护功能。我们的研究将为科学界开发一个有价值的资源-具有STC 2表达的空间和时间控制的转基因小鼠，并进行体外和体内可行性研究，这将提供证明STC 2对由Ca 2+稳态失调引起的细胞死亡的神经保护特性的原理证明。我们的研究结果将是至关重要的未来发展的STC 2为基础的治疗策略，以防止神经元死亡。