Uncovering the genetic mechanisms of the Chromosome 17q21.31 Tau haplotype on neurodegeneration risk in FTD and PSP

揭示染色体 17q21.31 Tau 单倍型对 FTD 和 PSP 神经变性风险的遗传机制

• 批准号: 10295512
• 负责人: DANIEL H GESCHWIND
• 金额: $ 189.28万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10295512
• 关键词: 17q21; 3-Dimensional; ATAC-seq; African; Alleles; Automobile Driving; Biological; Brain; CRISPR interference; CRISPR screen; Cell Communication; Cell Culture Techniques; Cell physiology; Cells; Chromatin Structure; Chromosome inversion; Chromosomes; Collaborations; Communication; Communities; Complex; Data; Dementia; Disease; Disease model; Enhancers; European; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional disorder; Future; Gene Abnormality; Gene Expression; Gene Expression Regulation; Gene Proteins; Genes; Genetic; Genetic Transcription; Genomics; Genotype; Glutamates; Goals; Haplotypes; Human; In Vitro; Individual; Induced pluripotent stem cell derived neurons; Inherited; Lead; Measures; Mediating; Methods; Molecular; Multiomic Data; Mutation; Nerve Degeneration; Neuroglia; Neurons; Nongovernmental Organizations; Nuclear; Pathogenesis; Pathologic; Pathway interactions; Phenotype; Post-Translational Protein Processing; Progressive Supranuclear Palsy; Proteomics; Public Domains; RNA Splicing; Recording of previous events; Regulator Genes; Regulatory Element; Research; Research Personnel; Risk; Role; Site; Stress; System; Tauopathies; Testing; United States National Institutes of Health; Validation; Variant; Work; brain tissue; causal variant; cell type; data resource; data sharing; disorder risk; distributed data; drug discovery; functional genomics; genetic association; human tissue; in vivo; induced pluripotent stem cell; meetings; molecular modeling; multiple omics; mutation carrier; new therapeutic target; programs; protein E; repository; tau Proteins; tau aggregation; tau phosphorylation; therapeutic development; tool; web site

PROJECT SUMMARY (OVERALL) Understanding the pathophysiology of dementia is often confounded by the uncertain causal roles of observed pathological phenotypes, even when highly correlated with disease. Genetic findings overcome these limitations by providing a causal anchor from which to begin mechanistic studies. In this regard, the genetic association between chromosome 17q21.31 and increased risk for tauopathies, including Frontotemporal Dementia (FTD) and Progressive Supranuclear Palsy (PSP), is well-established and striking. Despite this well-replicated association, little is known regarding mechanisms driving the differences in risk between the two major haplotypes, H1 and H2. This is in large part because this complex locus encompasses a genomic inversion of 970 KB, leading to an approximately 1.5Mb region where strong LD has confounded the identification of causal variants and understanding of the gene regulatory mechanisms contributing to disease. Here, we capitalize on recent advances in genomics to comprehensively characterize the genetic mechanisms by which this region, and the multiple loci within it, impart disease risk, thus identifying new targets for future therapeutic development. Our central hypothesis is that haplotype and cell type specific differences in gene expression and regulation, resulting from the H1/H2 genomic inversion lead to differences in risk for sporadic Tauopathies and differences in the effects of MAPT mutations associated with inherited forms of FTD. To test this hypothesis, we propose a multi-site, interdisciplinary center composed of two highly synergistic projects (P1, P2) and 4 cores (Proteomics, Human Tissue Validation, Data, Admin) integrating a highly complementary group of investigators with a strong history of collaboration and data sharing to connect multiple levels of function: a) genotype to b) chromatin structure to c) RNA expression and d) splicing, to protein and e) cell biological consequences to elucidate disease mechanisms. P1 will apply cutting edge multi-OMICs approaches in human induced pluripotent stem cell (iPSC)-derived neural cells and human brain tissue to determine the molecular and cellular mechanisms associated with the H1 and H2 haplotypes in individuals of European and African descent. Predicted regulatory element variation between haplotypes will be validated using a pooled CRISPR screen in assembloids. P2 uses parallel approaches to dissect the genetic mechanisms, cell types and molecular pathways involved in dominant forms of FTD-tau, and their modulation by the H1 and H2 haplotypes. Project 2 will use similar approaches to test whether H1/H2-associated differences in gene expression and regulation modulate the impact of FTD-associated MAPT mutations on disease-associated phenotypes and validate the impact of key haplotype specific enhancer/repressor regions using pooled Crispr i/a screens. Data and results generated from these projects will be integrated with existing publicly available data and distributed broadly to the research community. Understanding the mechanisms that lead from abnormal gene expression and protein modification, to tau aggregation and neurodegeneration will enable us to identify novel targets for drug discovery.

项目概要（总体） 了解痴呆症的病理生理学常常被观察到的不确定的因果作用所混淆。 病理表型，即使与疾病高度相关。遗传学发现克服了这些局限性 通过提供一个因果锚来开始机理研究。在这方面，遗传协会 染色体17q21.31与tau蛋白病风险增加之间的关系，包括额颞叶痴呆（FTD） 和进行性核上性麻痹（PSP），是公认的和惊人的。尽管这种复制良好的 关联，关于驱动两个主要风险之间差异的机制知之甚少。 单倍型，H1和H2。这在很大程度上是因为这个复杂的基因座包含了一个基因组倒位， 970 KB，导致约1.5 Mb区域，其中强LD混淆了因果关系的鉴定 变异和对导致疾病的基因调控机制的理解。在这里，我们利用 基因组学的最新进展，以全面表征该地区的遗传机制， 以及其中的多个基因座，赋予疾病风险，从而为未来的治疗开发确定新的靶点。 我们的中心假设是基因表达和调控的单体型和细胞类型特异性差异， H1/H2基因组倒位导致的散发性Tau病风险的差异和 与遗传性FTD相关的MAPT突变的影响。为了验证这一假设，我们提出了一个 由两个高度协同的项目（P1，P2）和4个核心（蛋白质组学， 人体组织验证、数据、管理），将高度互补的研究者团队与强大的 协作和数据共享的历史，以连接多个功能水平：a）基因型到B）染色质 结构到c）RNA表达和d）剪接，到蛋白质和e）细胞生物学后果， 阐明疾病机制。P1将在人类诱导的研究中应用最先进的多OMIC方法 多能干细胞（iPSC）衍生的神经细胞和人脑组织，以确定其分子和细胞功能。 与欧洲和非洲血统个体中H1和H2单倍型相关的机制。 预测的单倍型之间的调控元件变异将使用合并的CRISPR筛选进行验证， 类人猿P2使用平行的方法来剖析遗传机制，细胞类型和分子生物学。 参与FTD-tau显性形式的途径，以及H1和H2单倍型对它们的调节。计划2 将使用类似的方法来测试是否H1/H2相关的基因表达和调控的差异 调节FTD相关MAPT突变对疾病相关表型的影响，并验证 使用合并Crispr i/a筛选关键单倍型特异性增强子/阻遏子区域的影响。数据和结果 这些项目产生的数据将与现有的公开数据相结合，并广泛分发给 研究界。了解导致基因表达和蛋白质异常的机制 对tau聚集和神经退行性变的修饰将使我们能够识别药物发现的新靶点。