Coordination project

癫痫性疾病是一种常见的致残疾病，在世界范围内造成了重大的疾病负担。大规模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，我们的研究单位（RU）已经确定了几种新的疾病底物，这些底物是罕见和常见遗传因素在相同途径中聚集的。开发新的分析工具，如使用人类表型本体的平行保护或规模化表型，结合模型系统中的实验变异分析，已经揭示了基因和功能获得/丧失表型与管理和治疗的临床相关性。在动物模型中使用广泛的方法谱进行研究，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。这些都清楚地反映了在RU的所有项目中通过密切的交互和团队合作所带来的附加价值。我们已经确定了新的共同病理生理原理，例如不同斑马鱼和小鼠模型中树突树突和功能整合的改变，以及在明确的时间点发生癫痫发作的发育表型。由于遗传发现最初用于创建新的小鼠模型，现在可用于进一步研究，并且通过实施单细胞RNA测序（scRNA-seq）现在反馈到遗传研究中以寻找新的候选基因，因此两个方向都有一个连续的工作流程。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，包括对患者的重新利用和机械治疗。沿着这些思路，我们的首要目标将是在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揭示遗传决定的癫痫性级联，并将我们的发现应用于治疗干预。我们将(i)阐明罕见和常见形式的遗传性癫痫的“缺失遗传性”，使用前所未有的病例数，约50,000个样本，使我们能够接近具有常见和罕见变体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，以确定特定干预措施的关键时间窗口；（iii）将来自不同发育阶段动物模型的scRNA-seq数据与遗传数据相结合，以确定致癫痫的关键分子和途径；（iv）利用所获得的知识，将其转化为改进的疗法，包括药物治疗。rna靶向反义和启动子干扰系统。

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.