A "humanized" mouse model of Glut1 deficiency syndrome.

Glut1 缺乏综合征的“人源化”小鼠模型。

基本信息

批准号：
10506187
负责人：
Umrao Monani
金额：
$ 16.45万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10506187
关键词：
Address Adult Age Alzheimer&apos s Disease Astrocytes Behavioral Assay Blood Circulation Brain Brain Injuries Carrier Proteins Cellular Assay Cerebrum Cessation of life Childhood Chronic Coma Complex Consumption Development Diabetes Mellitus Disease Disease model Encapsulated Epilepsy Failure Family Functional disorder Future Generations Genes Glucose Glucose Transporter Health Human Impaired cognition Individual Intuition Light Malignant Neoplasms Mendelian disorder Molecular Movement Disorders Mus Neurons Organism Outcome Patients Phenotype Plant Roots Regulation Retinitis Pigmentosa Rodent SLC2A1 gene Seizures Syndrome Testing Therapeutic Therapeutic Agents Translating Violence Weight Work cerebral microvasculature deprivation disease phenotype early childhood effective therapy human model humanized mouse in vivo Model infancy mouse model novel preclinical study therapeutic evaluation therapy development tool

项目摘要

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.

项目摘要相对于它的大小，人的大脑消耗了大量人体总能量需要。这种能量主要以葡萄糖的形式传递，必须容易获得并提供给大脑按需。不这样做会对生物体产生可怕的后果，从而导致神经性糖性症，在严重的情况下，昏迷和死亡。而慢性的明显后果神经胶质细胞减少症 - 认知功能障碍 - 易于识别和建立良好的细胞和分子相关性尚未完全定义。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遗传确定的脑能量衰竭综合征。葡萄糖转运蛋白1缺乏综合征（GLUT1 DS）是典型的例子。由大脑的主要葡萄糖转运蛋白（GLUT1）的低水平，该疾病主要在婴儿期或早期打击童年时期，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的增长而恶化的复杂运动障碍。但是，没有真正有效的治疗方法可以解决 GLUT1 DS的根本原因，对分子和细胞机制的理解很少该疾病的表型表现。我们希望解决这些缺陷，并提出这样做的建议通过开发具有整个人类Glut1基因座的新型“人性化” GLUT1 DS模型的小鼠 - 该提议的目的。初步工作已经导致了这些小鼠的几行。在项目期间，我们将彻底描述小鼠，并采用了一部分已建立的分子，我们在实验室中优化的细胞和行为测定法。该项目的成功结果将导致在探测GLUT1 DS的基本机制的宝贵工具中，而且大脑较大的家族家族能量衰竭综合征。此外，预计小鼠将证明对GLUT1 DS治疗的发展有用。提高GLUT1水平是一种直观地出现的治疗策略，并且有可能这样做的药物最好在具有人类Glut1基因的体内模型中测试。