Modelling cerebellar pathology of Ataxia-Telangiectasia: Assessing ATM-deficient mice versus human iPS cells

共济失调毛细血管扩张症的小脑病理学建模：评估 ATM 缺陷小鼠与人类 iPS 细胞

• 批准号: 429443222
• 负责人: Professor Dr. Georg Auburger
• 金额: --
• 依托单位: Klinik für Neurologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/429443222?language=en
• 关键词: Modelling; cerebellar; pathology; Ataxia; Telangiectasia

Ataxia-telangiectasia (A-T) is caused by mutations in the ataxia-telangiectasia mutated (ATM) gene, which manifest in an autosomal recessive multi-system disorder, including neurological dysfunction. The best-studied function of ATM is a master controller of signal transduction for DNA damage response. However, additional and thus far poorly understood functions of ATM likely play critical roles in the neurodegenerative phenotype of A-T. Understanding the molecular basis of many diseases, including A-T, has been hampered by the lack of appropriate in vivo (animal) and in vitro (cell culture) models that accurately reflect the disease phenotypes. Importantly, reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) followed by generation of disease-relevant cell types in vitro provides an opportunity to gain insight into the molecular and cellular basis of disease. Neurological disorders in particular can greatly benefit from iPSC-disease modeling, because cell types of the central nervous system, such as neurons, are typically available only from post-mortem samples.In this project the two applicants build upon their complementary expertise (1) in mouse brain OMICS-level analysis of ataxia pathways affecting Purkinje neuron function and (2) in advanced genetic engineering of iPSCs. The aim of this project is to gain detailed insight into the cellular pathways affecting the neurodegenerative phenotype associated with A-T.Organotypic slice cultures established from Atm-/- mice will be employed to address DNA- and oxidative damage-induced cellular neuroinflammation and autophagy changes, as well as synaptic functions of ATM. Furthermore, transcriptome and proteome analyses of cerebellar samples of Atm-/- and wild-type mice will enable us to discover and annotate novel pathways and markers associated with neuronal functions of ATM in an unbiased manner. In parallel, isogenic pairs of patient-derived iPSC lines and their genetically corrected counterparts will be established for modeling A-T. The isogenic pairs of cell lines will be used to derive neuronal progenitors and characterized in vitro. The output of this project will provide valuable insights into the pathway mechanisms of disease, and cell-based models to investigate A-T-associated neurodegeneration, which may provide novel targets for future therapies.

共济失调 - 凝性（A-T）是由共济失调 - 塞氏症突变（ATM）基因突变引起的，该基因表现在常染色体隐性多系统疾病中，包括神经功能障碍。 ATM的最佳研究功能是DNA损伤响应信号转导的主控制器。然而，ATM的其他且迄今为止鲜为人知的功能可能在A-T的神经退行性表型中起关键作用。由于缺乏适当的体内（动物）和体外（细胞培养）模型，理解许多疾病的分子基础，这些疾病的分子基础受到阻碍，这些模型准确地反映了疾病表型。重要的是，将体细胞重编程为诱导的多能干细胞（IPSC），然后在体外产生与疾病相关的细胞类型，这为您提供了一个机会，可以深入了解疾病的分子和细胞基础。 Neurological disorders in particular can greatly benefit from iPSC-disease modeling, because cell types of the central nervous system, such as neurons, are typically available only from post-mortem samples.In this project the two applicants build upon their complementary expertise (1) in mouse brain OMICS-level analysis of ataxia pathways affecting Purkinje neuron function and (2) in advanced genetic engineering of iPSCs.该项目的目的是详细了解影响与ATM-/ - 小鼠建立的A-T.organotypic Slice培养物相关的神经退行性表型，将采用ATM-/ - 小鼠的培养物来解决DNA和氧化损伤诱导的细胞神经炎症和自动噬菌体的变化，以及自动噬菌体的变化，以及AINS的Synaptic formist ant Paintaptic功能。此外，对ATM - / - 和野生型小鼠小脑样品的转录组和蛋白质组分析将使我们能够以公正的方式发现和注释与ATM的神经元功能相关的新颖途径和标记。同时，将建立与患者衍生的IPSC线的等生成对及其遗传校正的对应物，用于建模A-T。细胞系的等源性对将用于得出神经元祖细胞并在体外表征。该项目的输出将为疾病的途径机理提供宝贵的见解，以及基于细胞的模型，以研究与A-T相关的神经变性，这可能为将来的疗法提供新的靶标。