CoEN: Investigating chromatin landscapes in neurodegenerative disease models

神经退行性疾病（ND）是高度衰弱的疾病，是发达国家的主要经济负担。虽然在控制症状方面取得了进展，但实际上不存在治疗这些病症的治疗选择。这是由于少数已知的ND引起的遗传变化及其作为治疗靶点的有限用途。因此，研究额外的非遗传性分子改变如何驱动ND的发生和进展至关重要。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已被认为有助于ND发病机制。然而，我们对ND相关染色质修饰的理解主要是基于对人死后组织的分析或体外临床前模型，这些模型并不能概括ND的复杂性。本申请旨在使用忠实的体内临床前模型提供ND发病过程中染色质变化的深入分析，并将这些变化与ND标志性病理特征相关联。总的来说，这项研究将为ND相关染色质改变的动态性质提供关键见解，并将构成进一步工作的基础，旨在确定治疗干预的新靶点。

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.