International Registry for Werner Syndrome

维尔纳综合症国际登记处

基本信息

批准号：
10563164
负责人：
JUNKO OSHIMA
金额：
$ 36.43万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-04 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10563164
关键词：
Abbreviations Acceleration Adult Affect Aging Autophagocytosis BSCL2 gene Basic Science Biocompatible Materials Biological Biology of Aging Blood specimen Categories Cell Culture Techniques Cells Chronic Clinic Clinical Clinical Trials Collaborations Cryopreservation Cultured Cells DNA Damage DNA Polymerase III DNA-Directed DNA Polymerase Development Dideoxy Chain Termination DNA Sequencing Disease Enrollment Epigenetic Process Exhibits FDA approved Family Family member Fibroblasts Follow-Up Studies Genes Genetic Genetic Diseases Genome Stability Genomic Instability Genotype Goals Human Inflammation International Janus kinase Japan Japanese Libraries Lipids Longevity MADH4 gene MDM2 gene Maintenance Malignant Neoplasms Manuscripts Mediating Metformin Microsatellite Instability Mitochondria Mutation Non-Insulin-Dependent Diabetes Mellitus Nuclear Nuclear Structure Nucleotide Excision Repair Oxidative Stress Parents Pathogenesis Pathogenicity Pathway interactions Patients Pharmaceutical Preparations Phenotype Plasma Play Polymerase Process Production Qualifying Rare Diseases Reagent Registries Regulation Research Resources Role STAT protein Series Siblings Signal Transduction Sirolimus Small Interfering RNA Specimen Syndrome TP53 gene Testing Therapeutic Therapeutic Agents Tissue Sample Transforming Growth Factor beta Translation Initiation Translational Research Variant WRN gene Washington Werner Syndrome age related biological research carcinogenesis causal variant clinical application comparative genomic hybridization comparison control cytokine disease phenotype efficacy evaluation established cell line exome exome sequencing experimental study gene discovery genetic analysis genetic pedigree genetic variant genome sciences genome sequencing genome-wide genomic locus helicase high throughput screening inhibitor kinase inhibitor mTOR Inhibitor member mutant new therapeutic target next generation sequencing nicotinamide-beta-riboside novel participant enrollment peripheral blood preclinical study recruit screening senescence synergism telomere therapeutic target transcriptome sequencing whole genome

项目摘要

Project Summary The International Registry of Werner Syndrome recruits cases of Werner syndrome (WS) and a range of other segmental progeroid syndromes from around the world with the goal of elucidating underlying mechanisms of accelerated aging. Detailed clinical information, the results of genetic analyses, and biological specimens are made available to a wide range of qualified geroscientists. In this application, we propose to extend our previous studies to include systematic genome-wide searches for the genetic variants responsible for the 78 progeroid cases that we have so far been unable to genetically characterize. An additional important extension of our research agenda is to initiate translational research that can lead to potential therapeutic agents. We will employ a combination of next generation sequencings, array CGH, and Sanger sequencing, followed by confirmatory Western analysis and quantitative PCR. These approaches have successfully identified novel pathogenic variants of WRN (a DNA helicase), LMNA (a component of nuclear structure), POLD1 (DNA polymerase delta), SPRTN (recruiter of DNA polymerase), ERCC4 (nucleotide excision repair), CTC1 (telomere replication), MDM2 (an inhibitor of P53) and SAMHD1 (regulation of dNTP pools). These loci highlight major roles for genome instability, now widely accepted as one of the hallmarks of aging. We also made progress in the identification of disease mutations that suggest other mechanisms of accelerated aging, such as BSCL2 (lipid droplet formation) and SMAD4 (intracellular signaling of a component of SASP, TGFβ). As indicated above, we will pursue translational research with the potential for the development of ameliorative therapies for our progeroid patients. Based on our previous studies, our collaborator, Dr. Yokote Koutaro at the Japanese Werner Consortium, is evaluating the efficacy of an NAD intermediate and an mTOR inhibitor, metformin, in WS patients. We shall begin independent studies of the effects of suppressors of chronic inflammation, namely Janus kinase (JAK) inhibitors, in cultures from WS patients and controls. This effort was motivated by our findings that SMAD4 mutant fibroblasts exhibited increased accumulation of DNA damage and that WRN mutant fibroblasts showed elevated SMAD4 expressions and dramatically higher levels of SASP compared to control cells, suggesting that a synergy of persistent DNA damage and inflammation may be one of the common key mechanisms leading to the accelerated aging. Concordant experiments will explore the effects of these novel therapeutic targets with high throughput screening of cell cultures from patients with other progeroid syndromes. An initial small scale experiment involving siRNA screening has revealed that siRNAs and drugs that alter the intranuclear dNTP concentration are able to modulate the cellular disease phenotypes of POLD1 mutants. Larger scale siRNA screening will be employed to identify additional novel relevant target pathways as well as previously unknown functional interactions of progeroid genetic loci.

项目摘要 Werner综合症国际注册表报告了Werner综合征（WS）的病例和A范围来自世界各地的其他节段孕制综合征的目的是阐明潜在的加速衰老的机制。详细的临床信息，遗传分析的结果和生物学标本可用于广泛的合格的Gerosciontist。在此应用中，我们建议将以前的研究扩展到包括系统的全基因组搜索负责我们迄今未能实现78例孕激素病例的遗传变异遗传表征。我们研究议程的另一个重要扩展是启动翻译可以导致潜在治疗剂的研究。我们将采用下一代测序，数组CGH和Sanger测序的组合，然后进行确认西方分析和定量PCR。这些方法已成功鉴定出WRN（DNA解旋酶），LMNA（核结构的一个成分）的新型致病变体， Pold1（DNA聚合酶三角洲），SPRTN（DNA聚合酶的招募者），ERCC4（核苷酸切除修复）， CTC1（端粒复制），MDM2（p53的抑制剂）和SAMHD1（DNTP池的调节）。这些基因座突出了基因组不稳定性的主要角色，现在被广泛接受为衰老的标志之一。我们也是在鉴定疾病突变的鉴定方面取得了进展，这些突变暗示了加速衰老的其他机制，例如BSCL2（脂质液滴形成）和SMAD4（SASP成分TGFβ的细胞内信号传导）。如上所述，我们将进行转化研究，以发展我们的后代患者的改善疗法。根据我们以前的研究，我们的合作者Yokote博士日本Werner财团的Koutaro正在评估NAD中级和MTOR的效率 WS患者的抑制剂二甲双胍。我们将开始对供应商的影响的独立研究慢性炎症，即WS患者和对照组的培养物中的Janus激酶（JAK）抑制剂。这我们的努力是由于我们发现SMAD4突变体成纤维细胞暴露增加了DNA的积累损坏和WRN突变体成纤维细胞显示了SMAD4表达式升高，并且高度更高与对照细胞相比，SASP的SASP，表明持续的DNA损伤和炎症的协同作用可能是导致加速衰老的常见关键机制之一。一致的实验将探索这些新型热目标的影响，并通过对细胞培养的高吞吐量筛选患有其他后代综合征的患者。涉及siRNA筛选的最初的小规模实验具有揭示了改变插图的siRNA和药物能够调节细胞 Pold1突变体的疾病表型。将雇用较大规模的siRNA筛选以识别新型相关目标途径以及先前未知的后代遗传基因座的功能相互作用。