International Registry of Werner Syndrome

维尔纳综合征国际登记处

• 批准号: 10344696
• 负责人: GEORGE M. MARTIN
• 金额: $ 21.77万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-18 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10344696
• 关键词: Adult; Award; Basic Science; Biocompatible Materials; Biological Aging; Biology of Aging; Cell Aging; Cell Line; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Cryopreservation; DNA Polymerase III; DNA Repair; DNA Repair Pathway; DNA biosynthesis; DNA-Directed DNA Polymerase; Development; Disease; Exonuclease; Funding; Gene Mutation; Genes; Genomic Instability; Genotype; International; MDM2 gene; Mutation; Nuclear; Nuclear Structure; Parents; Patients; Phenotype; Puberty; Registries; Regulation; Research Personnel; Resources; Role; SNP array; Symptoms; Syndrome; TP53 gene; Telomere Maintenance; Testing; Therapeutic Agents; Werner Syndrome; genetic pedigree; genome sequencing; genome-wide; helicase; human pluripotent stem cell; inhibitor/antagonist; next generation sequencing; novel; recruit; stem cells; transcriptome; whole genome

Project Summary of the Funded Parent Award The International Registry of Werner Syndrome & Related Disorders (www.wernersyndrome.org) serves as a resource to ascertain and genotype nuclear pedigrees segregating mutations responsible for Werner syndrome (WS) and a range of other segmental progeroid syndromes. We shall establish and cryopreserve biological materials from these pedigrees and provide them to investigators around the world. We now propose to conduct systematic genome-wide searches for the gene mutations responsible for 41 progeroid cases with unknown causes and to seek evidence for therapeutic agents. We will employ a combination of SNP arrays and next generation sequencing; these have successfully identified novel mutations in a small number of cases. Those findings continue to support the concept of genomic instability as a major mechanism of biological aging. These loci highlight major roles in DNA repair and replication: WRN (DNA helicase/exonuclease), POLD1 (DNA polymerase delta), and SPRTN (recruitment of translesional DNA polymerase); nuclear structure and chromatin interaction (LMNA); an inhibitor of p53 (MDM2); regulation of dNTP pools (SAMHD1); and telomere maintenance (CTC1). We will also investigate why WS phenotypes are manifested only after puberty. We hypothesize that there may be an activation of compensatory mechanisms such as other RecQ helicases or DNA repair pathways during early development. To test our hypothesis, we will generate human pluripotent stem cell lines with and without WRN disease mutations using human pluripotent stem cells (hPSCs) and CRISPR and conduct transcriptome studies. Analysis will focus on these questions: how other RecQ helicases and DNA repair related genes are expressed in WS hPSCs compared to control hPSCs, how these expressions change following differentiation; whether or not these expressions correlated with the expression of cellular senescence genes. Cell lines generated by this project and all available patient materials will be made available to other investigators.

资助家长奖项目概要 沃纳综合征及相关疾病国际登记处 (www.wernersyndrome.org) 作为确定和基因分型核谱系的资源，分离负责的突变 沃纳综合征 (WS) 和一系列其他节段性早衰综合征。我们将建立并 冷冻保存这些谱系的生物材料并将其提供给世界各地的研究人员。 我们现在建议进行系统的全基因组搜索，寻找导致这种现象的基因突变。 41例原因不明的早衰病例并寻求治疗药物的证据。我们将聘请一名 SNP 阵列和下一代测序的结合；这些已成功鉴定出新的突变 在少数情况下。这些发现继续支持基因组不稳定性作为主要因素的概念。 生物衰老的机制。这些基因座强调了 DNA 修复和复制中的主要作用：WRN（DNA 解旋酶/核酸外切酶）、POLD1（DNA 聚合酶 δ）和 SPRTN（跨损伤 DNA 募集） 聚合酶）；核结构和染色质相互作用（LMNA）； p53 (MDM2) 抑制剂；监管 dNTP 池 (SAMHD1)；和端粒维护（CTC1）。 我们还将研究为什么 WS 表型仅在青春期后显现。我们假设 可能会激活补偿机制，例如其他 RecQ 解旋酶或 DNA 修复 早期发育过程中的途径。为了检验我们的假设，我们将生成人类多能干细胞系 使用人类多能干细胞 (hPSC) 和 CRISPR 检测有或没有 WRN 疾病突变 进行转录组研究。分析将集中在以下问题：其他 RecQ 解旋酶和 DNA 如何 与对照 hPSC 相比，修复相关基因在 WS hPSC 中表达，这些表达如何变化 微分后；这些表达是否与细胞的表达相关 衰老基因。该项目产生的细胞系和所有可用的患者材料将被制作 可供其他调查人员使用。