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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：
10400381
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/10400381
关键词：
Acceleration Acetaldehyde Acute Myelocytic Leukemia Affect Age Aldehydes Allogenic Attention Award Biological Assay Blood Bone Marrow 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 Pancytopenia 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.

项目摘要该培训奖的总体目标是获得成为一名合格的具有骨髓衰竭基本机制研究专长的独立医生科学家，最终目标是开发新的疗法。维持基因组的完整性是细胞的一项重要任务，需要将正确的遗传信息传递给后代。细胞具有多种机制，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的影响损伤和依赖范可尼贫血DNA修复途径，消除DNA链间交联。患者缺乏范可尼贫血蛋白的人必然会出现骨髓衰竭。不幸的是没有治疗方法可以防止范可尼贫血的骨髓衰竭范可尼贫血的骨髓衰竭被认为是由DNA链间交联的不适当修复引起的，DNA损伤的来源是不太了解。最近的研究表明，内源性代谢副产物，如乙醛和甲醛加速范可尼贫血的疾病进展。来鉴定DNA的其他来源我们进行了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来进行适当的修复在这个应用程序中，我们建议验证我们的影响力使用体内移植试验和遗传学方法在小鼠造血干细胞中的体外发现改良的小鼠模型。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损伤源引起的基因组不稳定性。我们还将测试是否有任何其他的保护途径在造血干细胞的基因组维持中发挥作用。使用无偏倚的体内CRISPR筛选方法来筛选干细胞。通过学习获得的知识可以揭示了新的治疗靶点，可用于预防范可尼贫血和一般人口。