Genomics of DNA repair in the brain

保持基因组的保真度是一个基本的过程，特别是在大脑等组织中，由于高能量消耗，这些组织暴露在DNA损伤的水平上。DNA修复基因已经在非神经细胞类型和系中得到了广泛的研究。然而，在人类大脑中DNA修复过程的参与和调控方面存在着显著的知识差距。然而，干细胞和基因组方法学的进步正在为解决这些差距开辟新的途径。干细胞衍生的神经模型概括了人类生物学，并可与功能基因组筛选相结合，以了解这些系统中的重要基因。此外，大规模的神经基因组数据库继续增长并包含多样化的基因组信息。由于大脑是一个复杂的组织，利用这些发展来研究大脑中的DNA修复可以为这些复杂的通路如何在独特的细胞类型中进行调控提供重要的见解。目标：我的研究计划的长期目标是了解大脑中DNA修复的基本生物学。为了阐明这一点，我开发了一个双管齐下的方法，将利用以下平台：生物信息学工具(即计算分析)和体外模型(即人类干细胞衍生的神经模型)。因此，将实现以下短期目标：目标1：对高通量的功能基因组筛选和存储库进行生物信息学分析，以了解和优先处理与脑相关的DNA修复基因目标2：确定参与大脑DNA修复的神经细胞类型特定的生物过程计算分析将帮助我们了解大脑中与DNA修复相关的基本基因和过程。这些结果将被提供给验证实验，这些实验将在基因表达水平上评估基因敲除对人类脑细胞类型的影响，以了解调控这些基因的关键生物学过程。使用计算分析选择DNA修复基因进行功能跟踪(即生物信息学优先排序)，为更详细地研究与脑相关的DNA修复基因提供了一种经济有效的机制。影响：开发创新的生物信息学和功能基因组学平台将识别大脑中重要的DNA修复基因，并确定它们独特的基因组特征。功能实验将有助于确定它们在未被研究的人脑细胞中如何被调控的生物学机制。这些发现将与基因组学和神经科学领域特别相关。HQP将接受最新的生物信息学和包括神经模型在内的体外方法的培训。这些技能将为他们在学术界和工业界的职业生涯做好准备。加强加拿大对这些宝贵技能的培训能力，同时促进基因组学和DNA修复生物学的多样性，也将对自然科学产生重大影响。

Maintaining genome fidelity is an essential process, especially in tissues such as the brain, which are exposed to elevated levels of DNA damage due to high energy consumption. DNA repair genes have been extensively studied in non-neural cell types and lines. However, a significant knowledge gap exists in the involvement and regulation of DNA repair processes in the human brain. Advances in stem cell and genomic methodologies, however, are opening new avenues to address these gaps. Stem cell derived neural models recapitulate human biology and can be coupled with functional genomic screens to understand important genes in these systems. Further, large scale neurogenomic databases continue to grow and contain diverse genomic information. Since the brain is a complex tissue, harnessing these developments to study DNA repair in the brain can offer important insights into how these complex pathways are regulated in unique cell types. Objectives: The long-term objective of my research program is to understand the fundamental biology of DNA repair in the brain. To elucidate this, I have developed a two-pronged approach that will make use of the following platforms: bioinformatic tools (i.e., computational analyses) and in vitro models (i.e., human stem cell-derived neural models). The following short-term objectives will therefore be implemented: Objective 1: Perform bioinformatic analyses of high throughput functional genomic screens and repositories to understand and prioritize brain-relevant DNA repair genes Objective 2: Identify neural cell type specific biological processes involved in DNA repair in the brain The computational analyses will help us understand essential DNA repair-related genes and processes in the brain. These results will feed into validation experiments that will assess the impact of gene knockdown in human brain cell types at the level of gene expression to understand the key biological processes that regulate these genes. Using computational analyses to select DNA repair genes for functional follow up (i.e., bioinformatic prioritization), provides a cost-efficient and effective mechanism to study brain-related DNA-repair genes in greater detail. Impact: Developing innovative bioinformatics and functional genomics platforms will identify important DNA repair genes in the brain and determine their unique genomic characteristics. Functional experiments will assist in ascertaining the biological mechanisms underlying how they are regulated in understudied human brain cells. These findings will be especially relevant for the fields of genomics and neuroscience. HQP will be trained in latest bioinformatics and in vitro methods including neural models. These skills will equip them for careers in academia and industry. Enhancing the Canadian training capacity for these valuable skills, while promoting diversity in genomics and DNA repair biology, will also make a significant impact to the natural sciences.