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.

癫痫疾病是常见的，并且在全球范围内具有严重疾病的疾病。大规模的基因发现与机械研究相结合，大大加速了我们对基本原因的理解。在第一个资金期间，我们的研究部门（RU）确定了在同一途径中收敛的稀有遗传因素和常见遗传因素的几种新疾病底物。开发新的分析工具，例如使用人类表型本体论，例如模型系统中的实验变异分析，例如使用人类表型本体型，揭示了强大的基因和功能障碍 - 功能型 - 表型相关性与管理和治疗的临床相关性。在动物模型中使用跨RU的广泛方法学谱进行的研究，包括体外和体内电生理和成像技术，允许进行全面的分析，而这些分析本来不会成功的。这些清楚地反映了协作工作的附加值，并在RU的所有项目中进行了紧密的互动和团队合作。我们已经确定了新的常见病理生理学原理，例如在不同的斑马鱼和小鼠模型上改变树突状树皮和功能整合，以及在定义明确的时间点发生癫痫发作的发育表型。由于开始创建新的小鼠模型的遗传发现现在可用于进一步研究，并且通过实施单细胞RNA测序（SCRNA-SEQ），现在可以反馈到遗传研究中找到新的候选基因，这两个方向都有连续的工作流程。最后，将各种模型系统中的机制从单个细胞到小鼠在体内脱离了机制，使我们能够将这些发现转化为有效的治疗策略，包括重新锻炼和患者的机械疗法。沿着这些线路，我们的总体目标是在与持续的大脑发育和电路成熟的塑料环境中脱离遗传确定的癫痫发作的级联反应，并将我们的发现应用于治疗性干预措施。我们将（i）使用前所未有的病例数阐明罕见和常见形式的遗传性癫痫的“缺失”和常见的遗传性癫痫，有约50,000个样本，使我们能够处理具有常见和稀有变异的个体患者的整体综合燃烧，以确定其在新的遗传学上，以确定植物的遗传学症状，以确定其遗传学的遗传学差异，以确定其遗传学的含量，并确定遗传学的定位范围。干预措施，（iii）通过遗传数据在不同发育阶段的动物模型中综合的SCRNA-seq数据，以识别癫痫发作的关键分子和途径，并且（iv）（iv）利用获得的知识来转化为改进的治疗疗法，包括药物治疗，RNA靶向抗浓度和启动子干扰系统。