Mouse model for neuroprotection

神经保护小鼠模型

• 批准号: 7229860
• 负责人: GOPAL THINAKARAN
• 金额: $ 20.12万
• 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/7229860
• 关键词: Alzheimer' s Disease; Brain; Cell Death; Cell physiology; Cells; Cerebral Ischemia; Cerebral Ischemia-Hypoxia; Cessation of life; Communities; Complementary DNA; Condition; Cultured Cells; Cytoprotection; Development; Disease; Disruption; Elevation; Endoplasmic Reticulum; Environment; Feasibility Studies; Fishes; Fluorescence; Future; Genes; Glycoproteins; Goals; Homeostasis; Hormones; Hypoxia; In Vitro; Injury; Internal Ribosome Entry Site; Investigation; Ischemia; Lead; Mammals; Middle Cerebral Artery Occlusion; Molecular Chaperones; Mus; Neurodegenerative Disorders; Neuronal Injury; Neurons; Oranges; Organelles; Outcome; Oxidative Stress; Parkinson Disease; Pathway interactions; Physiological; Plasmids; Property; Prosencephalon; Protein Overexpression; Proteins; Relative (related person); Reporting; Research Personnel; Resources; Signal Pathway; Signal Transduction; Stimulus; Stress; Testing; Therapeutic; Thinking; Tissues; Transgenic Mice; Transgenic Organisms; base; cell injury; cofactor; in vivo; in vivo Model; mouse model; neuroprotection; novel; polyglutamine; prevent; promoter; protein misfolding; response; stanniocalcin 2

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）：CA2+稳态的障碍是瞬时缺血和几种神经退行性疾病的主要原因，例如阿尔茨海默氏病（AD），多谷氨酰胺疾病和帕金森病。内质网（ER）是Ca2+存储的主要细胞器。 ER通过CA2+信号传导调节多个细胞功能，并为跨膜和腔内蛋白的翻译后折叠和成熟提供了一种专门的环境。细胞内商店中Ca2+的损失会导致胞质Ca2+的升高，这可能导致因固有细胞死亡途径的激活而导致神经元脆弱性。此外，由于蛋白伴侣使用Ca2+作为辅因子，因此ER Ca2+的释放也通过积累错误折叠的蛋白质导致细胞损伤。扰动ER功能的生理，病理和实验条件会导致ER内错误折叠的蛋白的积累，并且由于随之而来的ER应力，激活了代偿信号传导途径，共同称为展开的蛋白质反应（UPR）。在此提案中，我们概述了基于Stanniocalcin 2（STC2）的过表达，概述了针对CA2+放松管制的小鼠模型的策略。我们最近将STC2鉴定为由哺乳动物UPR，缺氧和脑缺血引起的基因。我们进一步证明，在培养的细胞中，STC2的表达是必不可少的，足以提供对ER Ca2+稳态破坏引起的细胞死亡的细胞保护。 STC2是一种分泌的糖蛋白激素，在鱼类和哺乳动物中高度保守。我们假设STC2作为UPR的关键生存成分在哺乳动物中具有明显的功能，从而捍卫细胞免受病理条件下Ca2+稳态破坏引起的损伤。以下是该提案的具体目的：目标1。生成具有STC2表达的空间/时间控制的转基因小鼠。目标2。表征STC2的神经保护功能。我们的调查将为科学界 - 具有空间和时间控制STC2表达的转基因小鼠开发出宝贵的资源，并在体外和体外可行性研究中执行原理证明，以证明STC2的神经保护特性证明了通过对CA2+稳态解析而引发的细胞死亡。我们调查的结果对于预防神经元死亡的基于STC2的治疗策略的未来发展至关重要。