Sphingolipid Biology of Neurodegeneration

神经变性的鞘脂生物学

• 批准号: 9356148
• 负责人: Richard Proia
• 金额: $ 56.08万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9356148
• 关键词: Biological Models; Biology; Brain; Catabolism; Cell membrane; Cells; Cerebrum; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Defect; Development; Disease; Event; Family; Gangliosides; Gene Expression; Genes; Genetic Screening; Goals; Human; Inherited; Lead; Lipids; Membrane; Membrane Lipids; Modeling; Mus; Mutation; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Organoids; Patients; Process; Role; Sandhoff Disease; Signal Transduction; Sphingolipidoses; Sphingolipids; System; in vivo; induced pluripotent stem cell; sphingosine 1-phosphate; transcriptome sequencing

We are studying the events that occur due to the inability to degrade lipid substrated in the sphingolipidoses. We are using both mouse and human model systems. In the mouse system, we are using cultured neurons from a model model of Sandhoff disease and analyzing the changes in gene expression by RNA-seq. Functional assessment of the genes that are altered in the disease neurons will be accomplished by an in vivo pooled genetic screening approach. In the human system, iPS cells from a Sandhoff disease patient were edited with CRISPR/CAS9 to enable the correction of the HEXB gene. Using the Sandhoff disease and corrected iPS cells, cerebral organoids were produced. The organoids are being studied to identify changes caused by the genetic defect in Sandhoff disease that may lead to alterations in brain development.

我们正在研究由于无法降解鞘脂沉积中的脂质底物而发生的事件。 我们正在使用小鼠和人体模型系统。 在小鼠系统中，我们使用来自桑德霍夫病模型的培养神经元，并通过 RNA-seq 分析基因表达的变化。 对疾病神经元中改变的基因的功能评估将通过体内汇总遗传筛选方法来完成。 在人体系统中，来自桑德霍夫病患者的 iPS 细胞经过 CRISPR/CAS9 编辑，以校正 HEXB 基因。 利用桑德霍夫病和校正的 iPS 细胞，产生了大脑类器官。 正在研究这些类器官，以确定桑霍夫病遗传缺陷引起的变化，这些变化可能导致大脑发育的改变。