Coordination project

癫痫障碍是一种常见的致残性疾病，在全世界范围内都会造成严重的疾病负担。大规模的基因发现与机制研究相结合，极大地加快了我们对潜在原因的理解。在第一个资助期，我们的研究单位(RU)已经为罕见和常见的遗传因素在相同的途径上汇聚确定了几种新的疾病底物。发展新的分析工具，如利用人类表型本体论的Paralog保守或比例表型分析，结合模型系统中的实验变异分析，揭示了基因和功能获得/丧失表型与临床管理和治疗的相关性。在动物模型中进行的研究使用了广泛的方法学光谱，包括体外和体内的电生理和成像技术，允许进行个别小组无法实现的全面分析。这些都清楚地反映了协作工作的附加值，以及在RU所有项目中的密切交互和团队合作。我们已经确定了新的共同的病理生理学原理，例如在不同的斑马鱼和小鼠模型中改变的树突分枝和功能整合，以及在明确的时间点发生癫痫发作的发育表型。由于遗传学发现开始创造新的小鼠模型，现在可用于进一步研究，并通过实施单细胞RNA测序(scRNA-seq)现在反馈到遗传学研究，以寻找新的候选基因，在两个方向上都有持续的工作流程。最后，解开从单细胞到小鼠体内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，包括对患者的再利用和机械治疗。沿着这些思路，我们的首要目标将是解开与正在进行的大脑发育和电路成熟的可塑性环境的交叉点上由基因决定的致痫级联反应，并将我们的发现应用于治疗干预。我们将(I)使用史无前例的病例数量和约50,000个样本来阐明罕见和常见形式的遗传性癫痫的“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，以确定他们癫痫的类型和严重程度；(Ii)研究新发现的遗传缺陷的致痫机制，并在第一个资助期产生的动物模型中确定特定干预的关键时间窗口；(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治疗方法，包括药物治疗，RNA靶向反义和启动子干扰系统。

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.