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：
10902613
负责人：
DANIEL H GESCHWIND
金额：
$ 3.77万
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：
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/10902613
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 programs repository tau Proteins tau aggregation tau-1 therapeutic development tool web site

项目摘要

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）对痴呆症病理生理学的理解常常因观察到的不确定的因果作用而混淆。病理表型，即使与疾病高度相关。遗传学发现克服了这些限制通过提供一个因果锚点来开始机理研究。在这方面，遗传协会染色体 17q21.31 与 tau蛋白病（包括额颞叶痴呆 (FTD)）风险增加之间和进行性核上性麻痹（PSP），是既定且引人注目的。尽管这个复制得很好协会，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含基因组反转 970 KB，导致大约 1.5 Mb 的区域，其中强 LD 混淆了因果关系的识别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全面描述了该区域的遗传机制，以及其中的多个位点会带来疾病风险，从而确定未来治疗开发的新目标。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存在特异性差异， H1/H2 基因组倒位导致散发性 Tau蛋白病的风险差异和差异 MAPT 突变与遗传性 FTD 相关的影响。为了检验这个假设，我们提出了一个多地点、跨学科中心，由两个高度协同的项目（P1、P2）和 4 个核心项目（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团队与强大的连接多个功能级别的协作和数据共享历史：a) 基因型 b) 染色质 c) RNA 表达和 d) 剪接、蛋白质和 e) 细胞生物学后果阐明疾病机制。 P1 将应用最先进的多组学方法来研究人类诱导的多能干细胞 (iPSC) 衍生的神经细胞和人脑组织，以确定分子和细胞与欧洲和非洲血统个体的 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 CRISPR 筛选进行验证装配体。 P2 使用并行方法剖析遗传机制、细胞类型和分子涉及 FTD-tau 主导形式的途径，以及 H1 和 H2 单倍型对它们的调节。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控差异是否存在调节 FTD 相关 MAPT 突变对疾病相关表型的影响并验证使用汇集的 Crispr i/a 筛选对关键单倍型特异性增强子/阻遏子区域的影响。数据与结果这些项目产生的数据将与现有的公开数据相整合，并广泛分发给研究界。了解基因表达和蛋白质异常导致的机制对 tau 蛋白聚集和神经变性的修饰将使我们能够确定药物发现的新靶点。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dysregulated coordination of MAPT exon 2 and exon 10 splicing underlies different tau pathologies in PSP and AD.

MAPT 外显子 2 和外显子 10 剪接的失调协调是 PSP 和 AD 中不同 tau 病理学的基础。

DOI：
发表时间：
2022-02
期刊：
影响因子：
12.7
作者：
Bowles, Kathryn R;Pugh, Derian A;Oja, Laura;Jadow, Benjamin M;Farrell, Kurt;Whitney, Kristen;Sharma, Abhijeet;Cherry, Jonathan D;Raj, Towfique;Pereira, Ana C;Crary, John F;Goate, Alison M
通讯作者：
Goate, Alison M

Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases.

α-突触核蛋白、TDP-43 和 tau 突变通过减少溶酶体蛋白酶的降解来延长蛋白质半衰期。

DOI：
发表时间：
2023-05-02
期刊：
影响因子：
15.1
作者：
Sampognaro, Paul J;Arya, Shruti;Knudsen, Giselle M;Gunderson, Emma L;Sandoval;Hodul, Molly;Bowles, Kathryn;Craik, Charles S;Jacobson, Matthew P;Kao, Aimee W
通讯作者：
Kao, Aimee W

Towards elucidating disease-relevant states of neurons and glia by CRISPR-based functional genomics.

通过基于 CRISPR 的功能基因组学阐明神经元和神经胶质细胞的疾病相关状态。

DOI：
发表时间：
2022-11-18
期刊：
影响因子：
12.3
作者：
Leng, Kun;Kampmann, Martin
通讯作者：
Kampmann, Martin

Lysosomal proteomics reveals mechanisms of neuronal apoE4associated lysosomal dysfunction.

溶酶体蛋白质组学揭示了神经元 apoE4 相关溶酶体功能障碍的机制。

DOI：
发表时间：
2023-10-02
期刊：
影响因子：
0
作者：
Krogsaeter, Einar K;McKetney, Justin;Marquez, Angelica;Cakir, Zeynep;Stevenson, Erica;Jang, Gwendolyn M;Rao, Antara;Zhou, Anton;Huang, Yadong;Krogan, Nevan J;Swaney, Danielle L
通讯作者：
Swaney, Danielle L