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: 9341344
• 负责人: ALBEE MESSING
• 金额: $ 118.86万
• 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/9341344
• 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; Impairment; Intermediate Filament Proteins; Intermediate Filaments; Invertebrates; Investigation; Laboratories; Lead; Link; Monitor; Morphology; Mutation; Neurodegenerative Disorders; Pathologic; 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; misfolded protein; mouse model; mutant; neuron development; novel; programs; 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：亚历山大疾病是一种罕见且通常是致命的神经退行性疾病，是由编码III型中间丝蛋白GFAP的基因中的杂合突变引起的。该疾病的病理特征是Rosenthal纤维，一种含有中间丝的细胞质包容性和在整个中枢神经系统中积聚在星形胶质细胞中的小热激蛋白。我们小组的先前调查已让接受GFAP突变是几乎所有亚历山大病例的原因，并将这些信息迅速转化为临床实践作为诊断的标准。但是，GFAP突变引起星形胶质细胞功能障碍和疾病的机制尚不清楚。该计划项目的目标是开发人类星形胶质细胞的新型模型系统，研究突变GFAP和GFAP过量的星形胶质细胞对神经元发育，生存能力和功能的影响，并研究从大脑中清除错误折叠蛋白的途径。此外，我们将确定并表征疾病表型的遗传修饰符，并测试治疗的潜在策略。我们的研究涵盖了这些问题的遗传，生化，细胞，生理和形态学方法，并包括从无脊椎动物到人类的模型系统。该程序将链接四个实验室，一个使用人类诱导的多能干细胞，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，监控IACUC批准，并支持团体之间以及内部和外部咨询委员会之间的沟通。该计划将通过促进GFAP在疾病中的作用，通过在四个实验室之间的共享，通过思想的交叉侵入以及实验室成员之间的定期交流和会议来促进疾病在疾病中的作用。这些研究使人们对GFAP毒性的后果以及星形胶质细胞在大脑功能和疾病中的作用有新的见解。我们的希望是，此类研究最终将采用减轻星形胶质细胞功能障碍的毁灭性影响的策略。