EFRI CEE: Engineering and imaging 3D genome folding dynamics to control transcriptional misregulation in Alzheimer's disease

该项目旨在发现对阿尔茨海默病(AD)遗传缺陷的新的分子理解。AD是一种神经退行性疾病，在数百万美国人中逐渐破坏认知功能。研究小组将使用多学科方法和最先进的方法来测试与AD相关的基因的单碱基变化会改变基因组的三维(3D)包装或折叠，从而扰乱基因活动并导致神经元功能障碍的想法。同时，他们将建造和测试工具，将病理上纠缠在一起的DNA重新折叠成一种配置，从而逆转AD中功能不正常的基因的某些方面。该项目还将通过开发创新课程和培训机会产生教育影响，以吸引和留住下一代最高水平的人才，特别强调未被充分代表的少数群体，在新的基因组工程领域从事职业。从长远来看，研究和培训工作有可能为设计出更好的治疗阿尔茨海默病等疾病的药物做出积极贡献。一个关键的未知因素是，基因组非编码区中罕见而常见的单核苷酸变异是如何控制人类疾病中发生的基因表达失调的。这个项目的目标是阐明3D基因组和远程基因调控是如何被导致AD的遗传变异扰乱发育中的神经元的。该项目将重点研究3D表观基因组作为一个新的未探索的维度，以了解和逆转在散发性和家族性AD中出现的病理转录表型。在健康细胞和AD突变细胞的神经谱系承诺期间，尖端分子和成像技术将被用于以前所未有的分辨率和规模查询基因组折叠的结构和动力学。结果将被用来建立预测模型，以解释基因组错误连接是如何与病理性转录中断有关的。然后，将通过开发新的工程策略来测试这些模型，这些策略根据需要指导基因组拓扑的变化，以逆转转录缺陷。这项工作具有广泛的意义，因为它提供了新的量化模型和基因组工程工具，以揭示DNA序列的修改如何通过远程、高阶折叠机制来管理对正常神经元功能至关重要的基因表达谱。解决这一知识差距将为该团队设计3D基因组以控制衰弱的神经发育和神经退行性疾病中的神经细胞命运的长期目标提供必要的基础。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This project seeks to discover new molecular understanding of the genetic defects in Alzheimer's disease (AD), a neurodegenerative disorder that progressively disrupts cognitive function in millions of Americans. The research team will use multi-disciplinary approaches and state-of-the-art methods to test the idea that single-base changes in genes associated with AD alter the three-dimensional (3D) packaging or folding of the genome, thereby disrupting gene activity and causing neuronal dysfunction. In parallel, they will build and test tools to re-fold pathologically tangled DNA into a configuration that will reverse some aspects of the malfunctioning genes in AD. The project will also have educational impact through development of innovative courses and training opportunities to attract and retain the highest level of next-generation talent, with a particular emphasis on under-represented minorities, for careers in the new field of genome engineering. In the long term, the research and training efforts have the potential to make positive contributions towards engineering better medicines for diseases such as AD. A critical unknown is how rare and common single nucleotide variants in noncoding regions of the genome govern the misregulation of gene expression that occurs in human disease. The goal of this project is to elucidate how the 3D genome and long-range gene regulation is disrupted in developing neurons by the genetic variants that cause AD. The project will focus on investigating the 3D epigenome as a new unexplored dimension in understanding and reversing the pathological transcriptional phenotypes that occur in sporadic and familial forms of AD. Cutting-edge molecular and imaging technologies will be used to query the structure and dynamics of genome folding at unprecedented resolution and scale during neural lineage commitment in healthy cells and in cells with AD mutations. The resulting outcomes will be used to build predictive models to explain how genomic miswiring is linked to pathological transcriptional disruption. Then the models will be tested by developing new engineering strategies for directing changes in genome topology on demand to reverse transcriptional defects. This work is broadly significant because it provides new quantitative models and genome engineering tools to reveal how modifications to the DNA sequence work through long-range, higher-order folding mechanisms to govern the gene expression profiles critical for proper neuron function. Addressing this knowledge gap will provide an essential foundation for the team's long-term goal to engineer the 3D genome to control neural cell fate in debilitating neurodevelopmental and neurodegenerative diseases.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.