Coordination project

协调项目

• 批准号: 490944503
• 负责人: Professor Dr. Holger Lerche
• 金额: --
• 依托单位: Abteilung für Neurologie mit Schwerpunkt Epileptologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/490944503?language=en
• 关键词: Coordination; project

Epileptic disorders are common and disabling conditions with a significant disease burden worldwide. Large-scale gene discovery combined with mechanistic studies have greatly accelerated our understanding of underlying causes. In the 1st funding period, our Research Unit (RU) has identified several new disease substrates for both rare and common genetic factors converging in the same pathways. Developing new analysis tools, such as paralog conservation or scaled phenotyping using human phenotype ontology, combined with experimental variant analysis in model systems, have revealed strong gene-, and gain-/loss-of-function-phenotype correlations with clinical relevance for management and treatment. Studies in animal models using a broad methodological spectrum across the RU, including in vitro and in vivo electrophysiological and imaging techniques, allowed comprehensive analyses that would not have been achievable by individual groups. These clearly mirror the added value of the collaborative effort with close interactions and teamwork throughout all projects of the RU. We have identified novel common pathophysiological principles, such as altered dendritic arborization and functional integration across different zebrafish and mouse models and developmental phenotypes with seizures occurring at well-defined time points. Since genetic findings initiated to create new mouse models now being available for further studies, and through the implementation of single-cell RNA sequencing (scRNA-seq) now feeding back into genetic studies to find new candidate genes, there is a continuous workflow in both directions. Finally, disentangling the mechanisms in various model systems from single cells to mice in vivo allowed us to translate these findings into effective treatment strategies, including re-purposing and mechanistic therapies in patients. Along these lines, our overarching goal will be to unravel genetically determined epileptogenic cascades at the intersection with the plastic environment of ongoing brain development and circuit maturation, and apply our findings toward therapeutic intervention. We will (i) elucidate the ‘missing heritability’ in both rare and common forms of genetic epilepsies using unprecedented case numbers with ~50,000 samples allowing us to approach the overall integrated burden of individual patients with both common and rare variants to determine the type and severity of their epilepsy, (ii) study epileptogenesis for newly identified genetic defects and in animal models generated during the 1st funding period to identify critical time windows for specific interventions, (iii) integrate scRNA-seq data from animal models in different stages of development with genetic data to identify epileptogenic key molecules and pathways, and (iv) leverage the acquired knowledge for translation into improved therapies including pharmacological treatment, RNA-targeting antisense and promoter interference systems.

癫痫是一种常见的致残性疾病，在世界范围内造成了重大的疾病负担。大规模的基因发现与机制研究相结合，大大加快了我们对潜在原因的理解。在第一个资助期内，我们的研究单位（RU）已经确定了几种新的疾病底物，这些底物既有罕见的，也有常见的遗传因子，它们聚集在相同的途径中。开发新的分析工具，如parabolic保护或缩放表型使用人类表型本体，结合模型系统中的实验变异分析，揭示了强大的基因，和获得/丧失功能的表型与管理和治疗的临床相关性。在动物模型中使用RU的广泛方法学谱进行研究，包括体外和体内电生理和成像技术，允许进行单个组无法实现的全面分析。这些清楚地反映了在RU的所有项目中密切互动和团队合作的合作努力的附加值。我们已经确定了新的共同的病理生理学原理，如不同的斑马鱼和小鼠模型和发育表型与癫痫发作发生在明确的时间点，改变树突状分支和功能整合。由于遗传学发现开始创建新的小鼠模型，现在可用于进一步的研究，并通过实施单细胞RNA测序（scRNA-seq），现在反馈到遗传学研究中，以找到新的候选基因，在两个方向上都有一个连续的工作流程。最后，解开从单细胞到小鼠体内的各种模型系统中的机制，使我们能够将这些发现转化为有效的治疗策略，包括患者的再利用和机械治疗。沿着这些路线，我们的首要目标将是解开基因决定的癫痫级联反应与正在进行的大脑发育和回路成熟的塑性环境的交叉点，并将我们的发现应用于治疗干预。我们将（i）使用前所未有的病例数（约50，000个样本）阐明罕见和常见遗传性癫痫形式中的“缺失遗传性”，使我们能够接近具有常见和罕见变异的个体患者的总体综合负担，以确定其癫痫的类型和严重程度，（ii）研究新发现的遗传缺陷和在第一个资助期内产生的动物模型中的癫痫发生，以确定具体干预措施的关键时间窗口，（iii）将来自不同发育阶段的动物模型的scRNA-seq数据与遗传数据相结合，以确定致癫痫关键分子和途径，以及（iv）利用所获得的知识转化为改进的疗法，包括药物治疗，RNA靶向反义和启动子干扰系统。