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

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)

项目成果

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DANIEL H GESCHWIND其他文献

DANIEL H GESCHWIND的其他文献

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{{ truncateString('DANIEL H GESCHWIND', 18)}}的其他基金

Project 2: Impact of H1/H2 haplotypes on cellular disease-associated phenotypes driven by FTD-causing MAPT mutations
项目 2:H1/H2 单倍型对 FTD 引起的 MAPT 突变驱动的细胞疾病相关表型的影响
  • 批准号:
    10834336
  • 财政年份:
    2023
  • 资助金额:
    $ 189.28万
  • 项目类别:
UCLA High-Throughput Neuropsychiatric Disorder Phenotyping Center (UCLA HT-NPC)
加州大学洛杉矶分校高通量神经精神疾病表型中心 (UCLA HT-NPC)
  • 批准号:
    10643541
  • 财政年份:
    2023
  • 资助金额:
    $ 189.28万
  • 项目类别:
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:
    10789246
  • 财政年份:
    2023
  • 资助金额:
    $ 189.28万
  • 项目类别:
Project 2: Impact of H1/H2 haplotypes on cellular disease-associated phenotypes driven by FTD-causing MAPT mutations
项目 2:H1/H2 单倍型对 FTD 引起的 MAPT 突变驱动的细胞疾病相关表型的影响
  • 批准号:
    10295518
  • 财政年份:
    2021
  • 资助金额:
    $ 189.28万
  • 项目类别:
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:
    10902613
  • 财政年份:
    2021
  • 资助金额:
    $ 189.28万
  • 项目类别:
High-throughput Modeling of Autism Risk Genes using Zebrafish - DIVERSITY SUPPLEMENT
使用斑马鱼对自闭症风险基因进行高通量建模 - 多样性补充
  • 批准号:
    10818861
  • 财政年份:
    2020
  • 资助金额:
    $ 189.28万
  • 项目类别:
High-throughput modeling of autism risk genes using zebrafish
使用斑马鱼进行自闭症风险基因的高通量建模
  • 批准号:
    10478187
  • 财政年份:
    2020
  • 资助金额:
    $ 189.28万
  • 项目类别:
High-throughput modeling of autism risk genes using zebrafish
使用斑马鱼进行自闭症风险基因的高通量建模
  • 批准号:
    10121604
  • 财政年份:
    2020
  • 资助金额:
    $ 189.28万
  • 项目类别:
High-throughput modeling of autism risk genes using zebrafish
使用斑马鱼进行自闭症风险基因的高通量建模
  • 批准号:
    10264069
  • 财政年份:
    2020
  • 资助金额:
    $ 189.28万
  • 项目类别:
Genetic Investigation of Minimally Verbal Children with ASD
患有自闭症谱系障碍(ASD)的最少语言儿童的基因调查
  • 批准号:
    10470956
  • 财政年份:
    2019
  • 资助金额:
    $ 189.28万
  • 项目类别:

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