Alexander disease: mechanisms, modifiers, and therapeutics

亚历山大病：机制、修饰因素和治疗方法

• 批准号: 9134538
• 负责人: ALBEE MESSING
• 金额: $ 118.34万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-20 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9134538
• 关键词: Address; Advisory Committees; Alexander Disease; Animals; Astrocytes; Biochemical; Biological Models; Brain; Childhood; Communication; Cytoplasmic Inclusion; Disease; Drosophila genus; Fertilization; Fiber; Fostering; Functional disorder; Genes; Genetic; Glial Fibrillary Acidic Protein; Goals; Heat shock proteins; Human; IACUC; Intermediate Filament Proteins; Intermediate Filaments; Invertebrates; Investigation; Laboratories; Lead; Link; Monitor; Mutation; Neurodegenerative Disorders; Pathway interactions; Physiological; Rare Diseases; Reagent; Reporting; Role; Spinal Cord; Testing; Therapeutic; Toxic effect; Translations; Vertebrates; cell type; clinical practice; diagnosis standard; disease phenotype; induced pluripotent stem cell; insight; meetings; member; mouse model; mutant; neuron development; novel; programs; protein misfolding; public health relevance; treatment strategy

DESCRIPTION: Alexander disease is a rare and typically fatal neurodegenerative disease of childhood that results from heterozygous mutations in the gene encoding the type III intermediate filament protein GFAP. The pathological signature of the disorder is the Rosenthal fiber, a cytoplasmic inclusion containing intermediate filaments and small heat shock proteins that accumulates in astrocytes throughout the CNS. Prior investigations by our group have let to the acceptance of GFAP mutations as the cause for nearly all cases of Alexander disease, and the rapid translation of this information to clinical practice as the standard for diagnosis. However, the mechanisms by which GFAP mutations cause astrocyte dysfunction and disease remain unclear. The goals of this Program Project are to develop novel model systems of human astrocytes, investigate the impact of mutant GFAP and GFAP excess in astrocytes on neuronal development, viability, and function, and study the pathways by which mis-folded proteins are cleared from the brain. In addition, we will identify and characterize genetic modifiers of disease phenotype and test potential strategies for treatment. Our studies span genetic, biochemical, cellular, physiological, and morphological approaches to these questions, and include model systems ranging from invertebrate through human. The Program will link four laboratories, one using human induced pluripotent stem cells, one using Drosophila, and two using mouse models. An administrative core will coordinate financial reporting, monitor IACUC approvals, and support communication between the groups as well as with the internal and external advisory committees. The Program will promote a focused effort on the role of GFAP in disease, by fostering sharing of reagents, animals, and results among the four labs, through cross-fertilization of ideas, and by regular communication and meetings among laboratory members. These studies promise novel insights into the consequences of GFAP toxicity and the role of astrocytes in brain function and disease. Our hope is that such studies will ultimately lea to strategies for mitigating the devastating effects of astrocyte dysfunction.

描述：亚历山大病是一种罕见且通常致命的儿童神经退行性疾病，由编码 III 型中间丝蛋白 GFAP 的基因杂合突变引起。该疾病的病理特征是罗森塔尔纤维，这是一种细胞质内含物，含有中间丝和小的热休克蛋白，在整个中枢神经系统的星形胶质细胞中积累。我们小组之前的研究已经接受 GFAP 突变作为几乎所有亚历山大病病例的病因，并将这些信息快速转化为临床实践作为诊断标准。然而，GFAP 突变导致星形胶质细胞功能障碍和疾病的机制仍不清楚。该项目的目标是开发新型人类星形胶质细胞模型系统，研究星形胶质细胞中突变型 GFAP 和 GFAP 过量对神经元发育、活力和功能的影响，并研究从星形胶质细胞中清除错误折叠蛋白的途径。脑。此外，我们将识别和表征疾病表型的遗传修饰因子，并测试潜在的治疗策略。我们的研究涵盖了解决这些问题的遗传、生化、细胞、生理和形态学方法，包括从无脊椎动物到人类的模型系统。该计划将连接四个实验室，一个使用人类诱导多能干细胞，一个使用果蝇，两个使用小鼠模型。行政核心将协调财务报告、监督 IACUC 批准并支持各小组之间以及与内部和外部咨询委员会的沟通。该计划将通过促进四个实验室之间试剂、动物和结果的共享、思想的交叉传播以及实验室成员之间的定期沟通和会议，促进重点关注 GFAP 在疾病中的作用。这些研究有望对 GFAP 毒性的后果以及星形胶质细胞在脑功能和疾病中的作用产生新的见解。我们希望此类研究最终能够找到减轻星形胶质细胞功能障碍的破坏性影响的策略。