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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：
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
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/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

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.

项目总结（总体）