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Novel sources of endogenous DNA damage in hematopoietic stem progenitor cells

造血干祖细胞内源性 DNA 损伤的新来源

基本信息

批准号：
10490358
负责人：
Moonjung Jung
金额：
$ 23.55万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2021-09-20 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10490358
关键词：
Acceleration Acetaldehyde Acute Myelocytic Leukemia Affect Age Aldehydes Allogenic Attention Award Biological Assay Blood Bone Marrow Bone marrow failure CRISPR screen CRISPR/Cas technology Cell Death Cell Line Cells Clustered Regularly Interspaced Short Palindromic Repeats DNA Adducts DNA Damage DNA Interstrand Crosslinking DNA Repair Defect Disease Progression Drug Metabolic Detoxication Dysmyelopoietic Syndromes Engraftment Enzymes FANCD2 protein Fanconi Anemia Complementation Group A Protein Fanconi Anemia pathway Fanconi anemia protein Fanconi&apos s Anemia Formaldehyde Frequencies Functional disorder General Population Genes Genetic Genome Genomic Instability Goals Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human Impairment In Vitro Inherited Knock-out Knowledge Lead Lesion Maintenance Metabolic Modernization Monitor Mus Pathogenesis Pathway interactions Patients Physicians Play Prevention Reporting Research Ribonucleoproteins Risk Role Scientist Screening Result Solid Neoplasm Source Testing Training Transplantation Validation Variant Work acute T-cell lymphoblastic leukemia cell aldehyde dehydrogenases base bone marrow failure syndrome cell transformation cell type crosslink experience fitness genetic information genome integrity graft vs host disease hematopoietic tissue in vivo liquid chromatography mass spectrometry mortality mouse model new therapeutic target next generation sequencing novel novel therapeutics prevent repaired screening skills therapeutic target

项目摘要

Project Summary The overarching goal of this training award is to acquire the skills and experience necessary to become an independent physician scientist with research expertise on fundamental mechanisms of bone marrow failure, with a final goal of developing novel therapies. Maintaining genome integrity is an essential task for cells that need to pass correct genetic information to their progeny. Cells are equipped with a variety of mechanisms to protect their genome including robust DNA repair. Hematopoietic stem cells are especially vulnerable to DNA damage and rely on Fanconi anemia DNA repair pathway that removes DNA interstrand crosslinks. Patients lacking the Fanconi anemia proteins invariably develop bone marrow failures. Unfortunately, there is no therapy that prevents bone marrow failures in Fanconi anemia. While bone marrow failure in Fanconi anemia is thought to be caused by the inappropriate repair of the DNA interstrand crosslinks, the source of that DNA damage is poorly understood. Recent studies have implicated endogenous metabolic by-products, such as acetaldehyde and formaldehyde, in acceleration of disease progression in Fanconi anemia. To identify other sources of DNA damage, we have performed a CRISPR-Cas9 screen and identified a novel source of endogenous DNA damage that needs Fanconi anemia pathway for its proper repair. In this application, we propose to validate our impactful in vitro findings in the mouse hematopoietic stem cells using in vivo transplantation assays and genetically modified mouse models. We will also assess the type of DNA damage and subsequent cellular consequences, paying special attention to the genomic instability that is caused by this endogenous source of DNA damage. We will also test whether any other protective pathways play a role in genome maintenance of hematopoietic stem cells using an unbiased in vivo CRISPR screen approach. Knowledge gained through our studies may unveil novel therapeutic targets useful for prevention of bone marrow failures in Fanconi anemia and in the general population.

项目概要该培训奖的总体目标是获得成为一名技术人员所需的技能和经验。具有骨髓衰竭基本机制研究专业知识的独立医师科学家，最终目标是开发新疗法。维持基因组完整性是细胞的一项基本任务需要将正确的遗传信息传递给后代。细胞配备有多种机制保护他们的基因组，包括强大的 DNA 修复。造血干细胞特别容易受到 DNA 的影响损伤并依赖范可尼贫血 DNA 修复途径来消除 DNA 链间交联。患者缺乏范可尼贫血蛋白总是会导致骨髓衰竭。不幸的是，没有治疗方法可以预防范可尼贫血症中的骨髓衰竭。虽然范可尼贫血被认为是骨髓衰竭由 DNA 链间交联的不适当修复引起，DNA 损伤的根源是不太了解。最近的研究表明内源性代谢副产物，例如乙醛和甲醛，加速范可尼贫血的疾病进展。鉴定 DNA 的其他来源损伤，我们进行了 CRISPR-Cas9 筛选并确定了内源性 DNA 损伤的新来源需要范可尼贫血途径才能正确修复。在此应用程序中，我们建议验证我们的影响力使用体内移植试验和遗传方法对小鼠造血干细胞进行体外研究修改鼠标模型。我们还将评估 DNA 损伤的类型和随后的细胞后果，特别注意由这种内源性 DNA 损伤引起的基因组不稳定性。我们还将测试是否有任何其他保护途径在造血基因组维持中发挥作用使用无偏见的体内 CRISPR 筛选方法对干细胞进行筛选。通过我们的学习获得的知识可能揭示可用于预防范可尼贫血和骨髓衰竭的新治疗靶点一般人群。