Uncovering the Genetic Mechanisms of the Chromosome 17q21.31 Tau Haplotype on Neurodegeneration Risk in FTD and PSP

联系PD/PI：Goate，Alison M 项目总结(总体) 对痴呆症的病理生理学的理解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。基因研究结果克服了这些限制 通过提供一个因果锚，从那里开始机械学研究。在这方面，遗传关联 在染色体17q21.31与包括额颞性痴呆(FTD)在内的紧张性疾病风险增加之间 进行性核上性麻痹(PSP)是一种公认的、引人注目的疾病。尽管这一点得到了很好的复制 关于推动这两种主要疾病之间风险差异的机制，人们知之甚少 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 970kb，导致约1.5Mb的区域，其中强烈的LD混淆了原因的识别 变异和对致病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，以全面描述该区域、 以及其中的多个基因座，传递疾病风险，从而为未来的治疗开发确定新的靶点。 我们的中心假设是单倍型和细胞类型在基因表达和调控方面的特定差异， 由H1/H2基因组倒置导致的散发性转位病风险的差异和差异 与遗传性FTD相关的MAPT突变的影响。为了检验这一假设，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)将高度互补的研究人员小组与强大的 合作和数据共享的历史，以连接多个水平的功能：a)基因与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 阐明疾病的发病机制。P1将在人类诱导中应用尖端多组学方法 多能干细胞(IPSC)来源的神经细胞和人脑组织的分子和细胞测定 欧洲人和非洲人后裔中与H1和H2单倍型相关的机制。 单倍型之间预测的调控元件差异将使用中的汇集CRISPR屏幕进行验证 集合水滴。P2使用平行的方法来剖析遗传机制、细胞类型和分子 参与FTD-tau主要形式的途径，以及它们被H1和H2单倍型调控。项目2 将使用类似的方法来测试H1/H2在基因表达和调控方面的差异 调节FTD相关MAPT突变对疾病相关表型的影响并验证 使用池Crispr I/a筛选对关键单倍型特定增强子/抑制子区域的影响。数据和结果 从这些项目生成的数据将与现有的公开数据集成，并广泛分发到 研究界。了解基因表达和蛋白质异常导致的机制 对tau聚集和神经变性的修饰将使我们能够识别药物发现的新靶点。 项目摘要/摘要第72页

Contact PD/PI: GOATE, ALISON M 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. Project Summary/Abstract Page 72