International Registry of Werner Syndrome

维尔纳综合征国际登记处

• 批准号: 9275453
• 负责人: GEORGE M. MARTIN
• 金额: $ 35.34万
• 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 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275453
• 关键词: Adolescence; Adult; Affect; Aging; Aging-Related Process; Autophagocytosis; Basic Science; Biocompatible Materials; Biological Aging; Biology of Aging; Blood specimen; Cell Aging; Cell Line; Cells; Chromatin; Clinical; Clinical Data; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complementary DNA; Cryopreservation; Cultured Cells; DNA Polymerase III; DNA Repair; DNA Repair Gene; DNA Repair Pathway; DNA biosynthesis; DNA-Directed DNA Polymerase; Development; Disease; Family; Family member; Follow-Up Studies; Gene Expression; Gene Mutation; Genes; Genetic; Genome Stability; Genomic Instability; Genotype; Germany; Hereditary Disease; Human; International; Longevity; MDM2 gene; Maintenance; Mitochondria; Molecular Diagnosis; Molecular Profiling; Mutation; Nuclear; Nuclear Structure; Olives - dietary; Oxidative Stress; Parents; Pathogenesis; Patients; Phenotype; Plasma; Play; Process; Puberty; Rare Diseases; Reagent; Recruitment Activity; Registries; Regulation; Research Personnel; Resources; Role; SNP array; Series; Siblings; Stem cells; Symptoms; Syndrome; TP53 gene; Telomere Maintenance; Testing; Therapeutic Agents; Tissue Sample; Universities; Washington; Werner Syndrome; age related; biological research; carcinogenesis; clinical Diagnosis; comparative genomic hybridization; established cell line; gene discovery; genetic pedigree; genome sequencing; genome-wide; helicase; human embryonic stem cell; human pluripotent stem cell; inhibitor/antagonist; member; next generation sequencing; normal aging; novel; null mutation; peripheral blood; proteostasis; transcriptome; whole genome

Project Summary 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.

项目摘要 Werner综合征和相关疾病国际注册表（www.wernersyndrome.org） 作为确定和基因型核谱系的资源，隔离了负责的突变 Werner综合征（WS）和一系列其他节段的后代综合征。我们将建立和 来自这些血统的冷冻水果生物材料，并将其提供给世界各地的调查人员。 现在，我们建议对负责的基因突变进行系统的全基因组搜索 41个具有未知原因的后代病例，并寻求治疗剂的证据。我们将采用一个 SNP阵列和下一代测序的组合；这些成功鉴定了新的突变 在少数情况下。这些发现继续支持基因组不稳定性的概念 生物衰老的机制。这些基因座突出了DNA修复和复制中的主要作用：WRN（DNA 解旋酶/外切核酸酶），POLD1（DNA聚合酶三角洲）和SPRTN（跨性别DNA的募集 聚合酶）;核结构和染色质相互作用（LMNA）； p53的抑制剂（MDM2）;调节 DNTP池（SAMHD1）;和端粒维护（CTC1）。 我们还将研究为什么仅在青春期后才能表现出WS表型。我们假设这一点 代偿机制可能会激活其他RECQ解旋酶或DNA修复 早期发展期间的途径。为了检验我们的假设，我们将生成人类多能干细胞系 使用和不使用WRN疾病突变，使用人类多能干细胞（HPSC）和CRISPR和 进行转录组研究。分析将重点放在以下问题上：其他RECQ解旋酶和DNA如何 与对照HPSC相比，在WS HPSC中表达了相关基因，这些表达方式如何改变 差异化；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成 可供其他调查人员使用。