Molecular mechanisms of Werner syndrome helicase in genome stability and aging

维尔纳综合征解旋酶在基因组稳定性和衰老中的分子机制

基本信息

批准号：
10322752
负责人：
Michael Soniat
金额：
$ 10.8万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322752
关键词：
Aging Architecture Award Binding Binding Proteins Biochemical Biochemistry Biological Biological Models Biology Biophysics Bloom Syndrome Cell Aging Cell Line Cells Cellular biology Complement Complex Cryoelectron Microscopy DNA DNA Damage DNA Repair DNA Repair Enzymes DNA Repair Pathway DNA Structure Data Disease Exonuclease Family Foundations Functional disorder Future Genes Genome Genome Stability Genomic Instability Goals Hereditary Disease Heritability Human Human Biology Immune signaling Individual Inflammation Inflammatory Insecta Institution Interferons Length Maintenance Malignant Neoplasms Mentors Microscopy Molecular Molecular Biology Monitor Mutation Negative Staining Outcome PRKDC gene Pathology Pathway interactions Patients Phase Phenotype Play Positioning Attribute Premature aging syndrome Proteins Repair Complex Research Resolution Role Signal Transduction Stimulator of Interferon Genes Structure Syndrome TREX1 gene Testing Training Werner Syndrome Work age related base biophysical properties biophysical techniques career cytokine early onset exodeoxyribonuclease genome integrity helicase insight interdisciplinary approach mutant normal aging nuclease overexpression post-doctoral training premature prevent programs recruit replication factor A senescence sensor single molecule structural biology telomere telomere loss tenure track

项目摘要

PROJECT SUMMARY Progeroid syndromes mimic aging at an accelerated rate and are key to understanding both premature and normal aging. One class of progeroid syndromes results from defective DNA repair pathways. For example, Werner syndrome (WS)—a rare inherited disease characterized by premature aging and cancer—is caused by mutations in the DNA repair helicase WRN. WS patients closely recapitulate many normal aging phenotypes, making WS a model system for aging. However, the cellular and molecular mechanisms involved in WS pathologies remain poorly understood. Here, I propose to answer critical questions regarding the functions of WRN via an interdisciplinary approach that includes structural biology, single-molecule biochemistry, and cell biology. My career goal is to establish an independent research program dedicated to understanding the molecular and cellular mechanisms of genomic instability associated with aging and aging-related diseases. As a first step to achieving this goal, I have pursued postdoctoral training in single-molecule microscopy and biochemistry, complementing my background in structural biology and biophysical techniques. The mentoring phase of the K99/R00 award will provide me with additional training in cryo-electron microscopy, cell biology, telomere biology, and the biology of human aging through an expert group of mentors and advisors. Here I propose to: (1) Determine the molecular architecture of full-length WRN (2) Identify how the nuclease and helicase activities of WRN are regulated (3) Determine how WRN cooperates with telomeric proteins to unwind G-quadruplexes during telomere replication to prevent telomere loss, and (4) determine how WRN-deficiency leads to inflammation and premature cellular senescence. Completion of these aims will represent a major step forward in our understanding of WRN’s role in preventing genomic instability and will lay the groundwork for my long-term goals to determine the mechanisms of genome maintenance by other DNA repair enzymes and their importance in human aging and age-related pathologies. A K99/R00 award will allow me to establish an independent research program that will make me a strong candidate for a tenure-track position at a leading U.S. research institution. My work will provide important insights into how WRN and its interaction partners maintain our genomes and help us understand the biological consequences of WRN dysregulation. Furthermore, these studies will provide a more detailed understanding of how WRN-deficiency leads to accelerated aging phenotypes found in WS.

项目概要早衰综合症模仿加速衰老，是理解早衰和早衰的关键例如，一类早衰综合症是由 DNA 修复途径缺陷引起的。维尔纳综合征 (WS) 是一种罕见的遗传性疾病，其特征是过早衰老和癌症，由以下疾病引起： WS 患者的 DNA 修复解旋酶 WRN 突变与许多正常的衰老表型密切相关。使 WS 成为衰老的模型系统然而，WS 涉及的细胞和分子机制。在这里，我建议回答有关功能的关键问题。 WRN 通过跨学科方法，包括结构生物学、单分子生物化学和细胞生物学。我的职业目标是建立一个独立的研究项目，致力于了解与衰老和衰老相关疾病相关的基因组不稳定性的分子和细胞机制。实现这一目标的第一步是，我接受了单分子显微镜和生物化学，补充了我在结构生物学和生物物理技术方面的背景。 K99/R00 奖项的阶段将为我提供冷冻电子显微镜、细胞生物学、我在这里通过导师和顾问专家组研究端粒生物学和人类衰老生物学。建议： (1) 确定全长 WRN 的分子结构 (2) 确定核酸酶和 WRN解旋酶活性受到调节（3）确定WRN如何与端粒蛋白配合解旋端粒复制期间的 G-四链体以防止端粒丢失，以及 (4) 确定 WRN 缺陷如何导致炎症和细胞过早衰老。这些目标的完成将代表着重要的一步。加深了我们对 WRN 在防止基因组不稳定方面的作用的理解，并将为我的研究奠定基础确定其他 DNA 修复酶及其作用的基因组维护机制的长期目标在人类衰老和与年龄相关的病理学中具有重要意义。 K99/R00 奖项将使我能够建立一个独立的研究项目，这将使我成为一名强大的美国一家领先研究机构的终身职位候选人我的工作将提供重要的见解。了解 WRN 及其互动合作伙伴如何维护我们的基因组并帮助我们了解生物学此外，这些研究将提供对 WRN 失调的后果的更详细的了解。 WRN 缺陷如何导致 WS 中发现的加速衰老表型。