A "humanized" mouse model of Glut1 deficiency syndrome.

项目摘要 相对于它的大小，人脑消耗的能量占身体总能量的比例大得不成比例 需求这种能量主要以葡萄糖的形式输送，必须容易获得并供应给 按需大脑如果不这样做，会对生物体造成可怕的后果，导致一种 神经性低血糖症，并且在严重的情况下，昏迷和死亡。虽然慢性病的明显后果 神经性低血糖症-认知功能障碍-很容易识别和确立，其细胞和分子 相关因素尚未完全确定。了解机械细节的一种方法 潜在的大脑能量剥夺是通过研究基因决定的大脑能量衰竭 综合征葡萄糖转运蛋白-1缺乏综合征（Glut 1 DS）是典型的例子。造成 低水平的主要葡萄糖转运蛋白（Glut 1）的大脑，这种疾病主要发生在婴儿期或早期 儿童期，其特征是严重的癫痫发作、低脑葡萄糖、认知功能障碍和 随着年龄增长而出现的复杂的运动障碍。然而，没有真正有效的治疗方法， Glut 1 DS的根本原因，以及对导致Glut 1 DS的分子和细胞机制的了解很少。 疾病的表型表现我们希望解决这些不足之处，并建议这样做 通过开发携带整个人Glut 1基因座的新型“人源化”Glut 1 DS模型小鼠， 这一提议的目的。初步工作已经产生了几个品系的这种小鼠。期间 在项目期间，我们将彻底表征小鼠，采用一系列成熟的分子， 我们在实验室优化的细胞和行为分析。该项目的成功结果将导致 这是一个非常宝贵的工具，不仅可以探索Glut 1 DS的基本机制，还可以探索更大的大脑家族的基本机制。 能量衰竭综合征此外，预期小鼠在Glut 1 DS疗法开发中被证明是有用的; 提高Glut 1水平是一种直观上吸引人的治疗策略， 最好在具有人Glut 1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.