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.

项目总结