CoEN: Investigating chromatin landscapes in neurodegenerative disease models

神经退行性疾病(NDS)是高度衰弱的疾病，是发达国家的主要经济负担。虽然在药物控制症状方面取得了进展，但几乎没有治疗这些疾病的治疗选择。这是由于已知的导致ND的基因变化数量很少，而且它们作为治疗靶点的使用有限。因此，研究额外的、非遗传的分子改变如何驱动ND的启动和进展是至关重要的。在这方面，DNA在细胞核(染色质)中包装方式的改变及其对基因表达的影响被认为与ND的发病机制有关。然而，我们对ND相关的染色质修饰的理解主要是基于对人类死后组织的分析或基于体外临床前模型，这些模型不能概括NDS的复杂性。本应用的目的是利用忠实的在体临床前模型对ND发病过程中染色质的变化进行深入的分析，并将这些变化与ND标志的病理特征联系起来。总体而言，这项研究将为ND相关染色质改变的动态性质提供关键的见解，并将构成旨在确定新的治疗干预目标的进一步工作的基础。

Neurodegenerative diseases (NDs) are highly debilitating conditions that represent a major economic burden for the developed world. While progress has been made in controlling symptoms pharmacologically, virtually no therapeutic options exist for the treatment of these conditions. This is due to the small number of known ND-causing genetic changes and their limited use as therapeutic targets. It is therefore critical to investigate how additional, nongenetic molecular alterations can drive ND initiation and progression. In this respect, alteration of the way the DNA is packed in the nucleus (chromatin) and its consequences on gene expression have been suggested to contribute to ND pathogenesis. However, our understanding of NDassociated chromatin modifications is mostly based on analysis of human post-mortem tissues or on in vitro preclinical models that do not recapitulate the complexity of NDs. The present application aims to provide an in-depth analysis of chromatin changes over the course of ND pathogenesis using faithful in vivo preclinical models and to correlate these changes back to ND hallmark pathological features. Overall, this study will provide key insights into the dynamic nature of ND-associated chromatin alterations and will constitute the basis for further work aimed at identifying new targets for therapeutic intervention.