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

基本信息

批准号：
10789246
负责人：
DANIEL H GESCHWIND
金额：
$ 2.37万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10789246
关键词：
17q21 3-Dimensional ATAC-seq African African ancestry 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 European ancestry 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 Proteins Proteomics Public Domains RNA Splicing Recording of previous events Regulator Genes Regulatory Element Research Research Personnel Resources Risk Role Site Stress System Tauopathies Testing United States National Institutes of Health Validation Variant Visualization Work brain tissue causal variant cell type data integration 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 parent grant programs repository tau Proteins tau aggregation tau-1 therapeutic development tool web site

项目摘要

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

联系PD/PI：Goate，Alison M 项目摘要（总体）了解痴呆的病理生理学通常被观察到的不确定因果作用混淆即使与疾病高度相关，病理表型也是如此。遗传发现克服了这些局限性通过提供因果锚，可以从中开始机械研究。在这方面，遗传关联在17q21.31的染色体和tauopath的风险增加之间，包括额颞痴呆（FTD）和进步的上核麻痹（PSP）是完善的和惊人的。尽管这一重复了关联，关于驱动两个主要风险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括 970 kb，导致大约1.5MB的区域，在该区域中，强LD使因果关系识别变体和对导致疾病的基因调节机制的理解。在这里，我们大写基因组学的最新进展是全面地表征该区域的遗传机制以及其中的多个基因座，会带来疾病的风险，从而确定了未来治疗性发育的新目标。我们的中心假设是基因表达和调节中的单倍型和细胞类型特异性差异，由H1/H2基因组反转导致的导致偶发性扭曲和差异的风险差异在与FTD遗传形式相关的MAPT突变的影响中。为了检验这一假设，我们提出了一个多站点跨学科中心由两个高度协同的项目（P1，P2）和4个核心组成（蛋白质组学，，人体组织验证，数据，管理员）整合了高度互补的研究者，协作和数据共享的历史记录以连接多个功能级别：a）基因型b）染色质 c）RNA表达和d）剪接的结构，蛋白质和e）细胞生物学后果阐明疾病机制。 P1将在人类诱导的多能干细胞（IPSC）衍生的神经细胞和人脑组织，以确定分子和细胞欧洲和非洲血统中与H1和H2单倍型相关的机制。单倍型之间的预测调节元件变化将使用合并的CRISPR屏幕验证组合。 P2使用平行方法剖析遗传机制，细胞类型和分子涉及FTD-TAU的主要形式的途径，以及H1和H2单倍型的调节。项目2 将使用类似的方法来测试H1/H2相关的基因表达和调节差异调节FTD相关MAPT突变对疾病相关表型的影响，并验证使用合并的CRISPR I/A屏幕的关键单倍型特定增强器/阻遏物区域的影响。数据和结果从这些项目产生的研究界。了解从异常基因表达和蛋白质导致的机制修改，tau聚集和神经变性将使我们能够确定药物发现的新目标。项目摘要/摘要页面72