A "humanized" mouse model of Glut1 deficiency syndrome.

项目摘要 相对于它的大小，人脑消耗了人体总能量的不成比例的大量 需要。这种能量主要以葡萄糖的形式提供，必须随时可用并供应给 大脑随需应变。如果不这样做，对有机体会产生可怕的后果，导致一种 神经性低血糖，在严重情况下，昏迷和死亡。而慢性疾病的公开后果 神经性低血糖-认知功能障碍-很容易被识别并得到很好的证实，其细胞和分子 相关因素尚未得到充分定义。了解机械细节的一种方法 潜在的大脑能量匮乏是通过研究遗传决定的大脑能量衰竭来实现的 综合症。葡萄糖转运蛋白-1缺乏综合症(Glut1DS)就是一个典型的例子。起因于 脑部主要葡萄糖转运蛋白(Glut1)水平低，主要发病于婴儿期或早期 儿童时期，以严重癫痫发作、低脑血糖、认知功能障碍和 复杂的运动障碍，随着年龄的增长而恶化。然而，还没有真正有效的治疗方法来解决 Glut1DS的根本原因，以及对导致Glut1DS的分子和细胞机制知之甚少 这种疾病的表型表现。我们希望解决这些不足之处，并提议这样做 通过开发具有完整人类Glut1基因座的新型人源化Glut1DS模型小鼠- 这项提议的目的。初步工作已经培育出了几个品系的这种小鼠。在.期间 在项目期间，我们将利用成熟的分子电池，对小鼠进行彻底的鉴定， 我们在实验室中优化的细胞和行为分析。该项目将取得成功的结果 这是一个非常有价值的工具，不仅可以探索Glut1DS的基本机制，还可以探索更大的大脑家族的基本机制 能源衰竭综合症。此外，这些小鼠有望在Glut1DS治疗开发中发挥作用； 提高Glut1水平是一种直观上有吸引力的治疗策略和有潜力这样做的药物 最好是在被赋予人类Glut1基因的体内模型中进行测试。

Project Summary Relative to its size, the human brain consumes a disproportionately large quantity of the body’s total energy needs. This energy, delivered mainly in the form of glucose, must be readily available and supplied to the brain on-demand. Failure to do so has dire consequences for the organism, resulting in a state of neuroglycopenia and, in severe instances, coma and death. While the overt consequence of chronic neuroglycopenia – cognitive dysfunction – is easily recognized and well-established, its cellular and molecular correlates are yet to be fully defined. One way of gaining an understanding of the mechanistic details underlying brain energy deprivation is through the study of genetically determined brain energy failure syndromes. Glucose Transporter-1 deficiency syndrome (Glut1 DS) is the quintessential example. Caused by low levels of the principal glucose transporter (Glut1) of the brain, the disease strikes mainly in infancy or early childhood and is characterized by severe epileptic seizures, low brain glucose, cognitive dysfunction and a complex movement disorder that worsens with age. Yet, there is no truly effective treatment that addresses the root cause of Glut1 DS, and little understanding of the molecular and cellular mechanisms that account for the phenotypic presentation of the disease. We wish to address these deficiencies, and propose to do so through the development of novel “humanized” Glut1 DS model mice harboring the entire human Glut1 locus – the objective of this proposal. Preliminary work has already resulted in several lines of these mice. During the project period, we will thoroughly characterize the mice, employing a battery of well-established molecular, cellular and behavioral assays that we have optimized in the lab. A successful outcome to the project will result in an invaluable tool to probe basic mechanisms underlying not just Glut1 DS but also the larger family of brain energy failure syndromes. Moreover, the mice are expected to prove useful in Glut1 DS therapy development; raising Glut1 levels is an intuitively appealing therapeutic strategy and agents that have the potential to do so are best tested in an in vivo model endowed with the human Glut1 gene.