Mapping cell-type-specific regulatory genomic variation in Alzheimer's disease pathology.

阿尔茨海默病（AD）是一种慢性神经退行性疾病，影响全球超过2600万人，没有可用的疾病修饰治疗。尽管在识别AD的遗传风险因素方面取得了重大进展，但有关所涉及的特定致病基因以及它们的功能在神经病理学进展期间如何失调仍然存在不确定性。对基因组进行测序只是我们探索基因如何表达和调控的第一步。对基因组功能复杂性的了解增加，导致人们认识到调节变异在健康和疾病中的作用。位于DNA序列之上的是第二层信息（“表观基因组”），它调节基因在何时何地进行功能性转录。这些机制在确定人脑中基因转录的细胞类型特异性模式中起着关键作用。以前的AD脑基因组分析受到使用“大块”组织的限制，包括不同神经细胞类型的混合。由于AD的特征在于特定细胞类型的变化（例如，它涉及神经元的大量损失和神经胶质细胞的增殖），因此考虑基因调控中的细胞差异至关重要。我们的研究将首次系统地研究AD病理学中特定细胞类型中调控基因组过程的作用。我们的创新提案利用了英国目前正在进行的前所未有的脑银行工作，特别是在痴呆症研究（BDR）队列中。我们提出了一个整合的基因组学方法，分析纯化的皮质细胞核的人口从捐助者与低和高水平的AD病理。我们的项目有以下主要aimsFirst，我们将概况表观基因组调控标记纯化的核从三种不同的细胞类型（神经元，少突胶质细胞和小胶质细胞）分离皮质组织从捐助者与低和高水平的AD病理。其次，我们将在其他样本和数据集中验证与AD病理学相关的调控区域。第三，我们将研究AD相关的遗传变异如何影响特定皮质细胞类型的基因调控。我们的团队是唯一能够承担这个雄心勃勃的项目的人，因为我们的开创性工作评估了AD大脑中的表观基因组变异，我们在开发不同神经细胞类型的调控基因组分析的新方法中发挥了作用。最后，我们是开放科学的热情倡导者，我们将向更广泛的研究界免费提供所有数据和方法。结合研究中收集的每个捐赠者的广泛临床和神经病理学数据，我们将产生一个无与伦比的数据资源，这将刺激痴呆症研究，并使对AD所涉及的机制途径的理解发生飞跃。

Alzheimer's disease (AD) is a chronic neurodegenerative disorder affecting >26 million people worldwide, with no disease-modifying treatments available. Despite major advances in identifying genetic risk factors for AD, there remains uncertainty about the specific causal genes involved and how their function is dysregulated during the progression of neuropathology. Sequencing the genome was only the first step in our quest to understand how genes are expressed and regulated. Increased understanding about the functional complexity of the genome has led to recognition about the role of regulatory variation in health and disease. Sitting above the DNA sequence is a second layer of information (the 'epigenome') that mediates the regulation of when and where genes are functionally transcribed. These mechanisms play a critical role in determining cell-type-specific patterns of gene transcription in the human brain.Previous genomic analyses of AD brain have been limited by their use of 'bulk' tissue, comprising a mix of different neural cell-types. Because AD is characterised by changes in specific cell-types (for example it involves the extensive loss of neurons and the proliferation of glial cells) it is critical to consider cellular differences in gene regulation. Our study will, for the first time, systematically examine the role of regulatory genomic processes in specific cell types in AD pathology.Our innovative proposal leverages the unprecedented brain-banking efforts currently taking place in the UK, specifically within the Brains for Dementia Research (BDR) cohort. We propose an integrative-genomics approach, profiling purified populations of cortical nuclei from donors with low and high levels of AD pathology. Our project has the following key aimsFirst, we will profile markers of epigenomic regulation in purified nuclei from three different cell types (neurons, oligodendrocytes and microglia) isolated from cortex tissue from donors with low and high levels of AD pathology. Second, we will validate regulatory regions associated with AD pathology in additional samples and datasets. Third, we will examine how AD-associated genetic variation influences gene regulation in specific cortical cell-types.Our team is uniquely placed to undertake this ambitious project given our pioneering work assessing epigenomic variation in AD brain and our role in developing novel methods for regulatory genomic profiling across distinct neural cell-types.Finally, we are passionate advocates for Open Science, and we will make all data and methods freely available to the wider research community. In conjunction with the extensive clinical and neuropathological data being collected on each donor included in the study, we will generate an unrivalled data resource that will stimulate dementia research and enable a step-change in understanding of the mechanistic pathways involved in AD.