Understanding the aging process in hematopoietic stem cells by alcohol-induced DNA damage

了解酒精诱导的 DNA 损伤造血干细胞的衰老过程

基本信息

批准号：
10811164
负责人：
Moonjung Jung
金额：
$ 23.54万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10811164
关键词：
8-hydroxy-2&apos -deoxyguanosine Acceleration Acetaldehyde Address Aging Alcohol consumption Alcohol-Induced Disorders Alcoholic Hepatitis Alcohols Anemia Animal Model Base Excision Repairs Bone Marrow Bone Marrow Suppression Bone Marrow Transplantation Bone marrow failure Brain CRISPR screen Cell Aging Cell Line Cells Chronic DNA Damage DNA Markers DNA Repair DNA Repair Gene DNA Repair Pathway DNA lesion Data Dose Dysmyelopoietic Syndromes Epigenetic Process Fanconi&apos s Anemia Funding Future Gamma-H2AX General Population Genes Genetic Genome Genomics Germ-Line Mutation Goals Health Heavy Drinking Hematologic Neoplasms Hematopoiesis Hematopoietic Hematopoietic stem cells Human Human Cell Line In Vitro Individual Inflammation Iron Japanese Jurkat Cells Knowledge Lesion Leukopenia Light Literature Liver Liver diseases Metabolic Mitochondria Mitochondrial DNA Modeling Mus Mutate Myelogenous National Institute on Alcohol Abuse and Alcoholism Organ Pancytopenia Pathway interactions Patients Physicians Play Population Populations at Risk Premature aging syndrome Prevalence Prevention Principal Investigator Process Rattus Reactive Oxygen Species Research Research Personnel Reticulocyte count Risk Rodent Model Scientist Source Speed Testing Thrombocytopenia Up-Regulation Variant Work age related aged aging population alcohol abuse therapy alcohol effect alcohol exposure alcohol prevention alcohol research alcohol risk alcohol sensitivity chronic alcohol ingestion detection of nutrient dietary supplements drinking exhaustion feeding folic acid metabolism genetic variant genome integrity hematopoietic stem cell aging insight liver transplantation mouse model new therapeutic target oxidative DNA damage prevent problem drinker repair function repaired response single-cell RNA sequencing stem cell population stem cells therapeutic target transplant model

项目摘要

Project Summary Alcohol is a common potential source of DNA damage in humans. Indeed, its metabolic byproducts, acetaldehyde and reactive oxygen species (ROS), mutate hematopoietic stem cells (HSCs). Importantly, DNA damage is central to the aging process by contributing to stem cell exhaustion, cellular senescence, inflammation, and deregulated nutrient sensing. Together, these findings have led us to hypothesize that alcohol-induced DNA damage accelerates aging in HSCs. Moreover, aged HSCs have myeloid-biased differentiation, reduced long- term repopulating potential and decreased DNA repair function, which may lend themselves to being more vulnerable to alcohol-induced DNA damage. Prior research has used very high doses of alcohol to study their DNA-damaging effects on HSCs, which is difficult to generalize to the broader aging population who may enjoy only moderate alcohol drinking. Also, the effects of moderate alcohol consumption on overall health in the general population remain controversial. The overarching goal of this proposal is to shed light on the key aspects of HSC aging using cell-based and animal models. We aim to identify DNA repair genes essential for repairing alcohol- induced DNA damage in HSCs by a pooled CRISPR screen. We also aim to determine whether aged HSCs are more vulnerable to moderate alcohol drinking using a mouse bone marrow transplant model and a single-cell RNA-sequencing approach. Our proposed studies will reveal genes that repair DNA lesions caused by alcohol and its toxic metabolic by-products. It will also inform us how aged HSCs respond differently to alcohol-induced DNA damage than younger HSCs. Identification of key differences in DNA damage response and DNA repair in aged HSCs will enable us to uncover ways to prevent aging due to alcohol and potentially due to other endogenous and exogenous DNA damaging agents as well.

项目概要酒精是人类 DNA 损伤的常见潜在来源。事实上，它的代谢副产物，乙醛和活性氧 (ROS) 会导致造血干细胞 (HSC) 突变。重要的是，DNA 损伤是衰老过程的核心，会导致干细胞衰竭、细胞衰老、炎症、和解除对营养物传感的管制。总之，这些发现使我们推测酒精诱导的 DNA 损伤会加速造血干细胞的衰老。此外，衰老的 HSC 具有髓系偏向分化，减少了长术语重新繁殖潜力和 DNA 修复功能下降，这可能会使它们变得更加容易受到酒精引起的 DNA 损伤。先前的研究使用了非常高剂量的酒精来研究它们的 DNA 损伤对 HSC 的影响，很难推广到更广泛的老年人群仅适度饮酒。此外，适度饮酒对总体健康的影响人口仍存在争议。该提案的总体目标是阐明 HSC 的关键方面使用基于细胞和动物模型的衰老。我们的目标是识别修复酒精所必需的 DNA 修复基因通过混合 CRISPR 筛选在 HSC 中诱导 DNA 损伤。我们还旨在确定老化的 HSC 是否使用小鼠骨髓移植模型和单细胞更容易受到适度饮酒的影响 RNA测序方法。我们提出的研究将揭示修复酒精引起的 DNA 损伤的基因及其有毒的代谢副产物。它还将告诉我们衰老的 HSC 对酒精诱导的反应有何不同 DNA 损伤比年轻的 HSC 更严重。鉴定 DNA 损伤反应和 DNA 修复的关键差异老化的 HSC 将使我们能够找到预防因酒精和其他原因引起的衰老的方法。内源性和外源性 DNA 损伤剂。