Document text
Principal Investigator: Moonjung Jung
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $194,453
Funding agency: National Institute on Alcohol Abuse and Alcoholism
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.
Terms: <2'-deoxy-8-hydroxyguanosine><8-OH-dG><8-hydroxy-2'-deoxyguanosine><8-hydroxydeoxyguanosine><8-oxodGuo><Acetaldehyde><Active Oxygen><Address><Aging><Alcohol Chemical Class><Alcohol Drinking><Alcohol associated hepatitis><Alcohol consumption><Alcohol hepatitis><Alcohol induced hepatitis><Alcohol related hepatitis><Alcohol-Induced Disorders><Alcoholic><Alcoholic Hepatitis><Alcohols><Anemia><Animal Model><Animal Models and Related Studies><Base Excision Repairs><Blood Precursor Cell><Bone Marrow><Bone Marrow Grafting><Bone Marrow Reticuloendothelial System><Bone Marrow Suppression><Bone Marrow Transplant><Bone Marrow Transplantation><Bone marrow failure><Boozer><Brain><Brain Nervous System><CRISPR editing screen><CRISPR screen><CRISPR-based screen><CRISPR/Cas9 screen><Cell Aging><Cell Body><Cell Line><Cell Senescence><CellLine><Cells><Cellular Aging><Cellular Senescence><Chronic><Common Rat Strains><Congenital Pancytopenia><DNA Base Excision Repair><DNA Damage><DNA Damage Repair><DNA Injury><DNA Repair><DNA Repair Gene><DNA Repair Pathway><DNA lesion><DNA repair protein><Data><Dependent drinker><Dose><Dysmyelopoietic Syndromes><Encephalon><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><EtOH drinking><EtOH use><Ethanal><Ethanol-induced hepatitis><Fanconi Anemia><Fanconi Panmyelopathy><Fanconi dysplasia><Fanconi's Anemia><Fe element><Folate Metabolism><Folic Acid Metabolosm><Funding><Future><Gamma-H2AX><Gene variant><General Population><General Public><Genes><Genetic><Genome><Genomics><Germ-Line Mutation><Germline Mutation><Goals><Groups at risk><HSC aging><Health><Heavy Drinking><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoiesis><Hematopoietic><Hematopoietic Cancer><Hematopoietic Cellular Control Mechanisms><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Hepatic Disorder><Hepatic Transplantation><Hereditary Mutation><Human><Human Cell Line><In Vitro><Individual><Inflammation><Investigators><Iron><Japanese><Jurkat Cells><Knowledge><Lesion><Leukocytopenia><Leukopenia><Light><Literature><Liver><Liver Grafting><Liver Transplant><Liver diseases><Malignant Hematologic Neoplasm><Marrow Transplantation><Metabolic><Mice><Mice Mammals><Mitochondria><Mitochondrial DNA><Modeling><Modern Man><Murine><Mus><Mutate><Myelodysplastic Disease><Myelodysplastic Syndromes><Myelogenous><Myeloid><NIAAA><National Institute on Alcohol Abuse and Alcoholism><Older Population><Organ><Oxygen Radicals><Pancytopenia><Pathway interactions><Patients><People at risk><Persons at risk><Photoradiation><Physicians><Play><Population><Populations at Risk><Premature Aging><Premature aging syndrome><Prevalence><Prevention><Primary Erythroid Hypoplasia><Principal Investigator><Pro-Oxidants><Rat><Rats Mammals><Rattus><Reactive Oxygen Species><Refractory Anemia with an Excess of Blasts><Refractory anaemia with excess blasts><Replicative Senescence><Research><Research Personnel><Researchers><Reticulocyte Number><Reticulocyte count><Risk><Rodent Model><Scientist><Smoldering Leukemia><Source><Strains Cell Lines><Testing><Thrombocytopenia><Thrombopenia><Unscheduled DNA Synthesis><Up-Regulation><Upregulation><Variant><Variation><Work><accelerated aging><accelerated biological age><accelerated biological aging><age acceleration><age associated><age correlated><age dependent><age linked><age related><age specific><aged><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><aging associated><aging population><aging process><aging related><alcohol abuse therapy><alcohol abuse treatment><alcohol effect><alcohol exposed><alcohol exposure><alcohol induced injury><alcohol ingestion><alcohol intake><alcohol prevention><alcohol product use><alcohol related research><alcohol research><alcohol risk><alcohol sensitivity><alcohol treatment><alcohol use><alcohol-induced damage><alcoholic beverage consumption><alcoholic drink intake><allele variant><allelic variant><blood cell formation><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><chronic EtOH drinking><chronic alcohol consumption><chronic alcohol drinking><chronic alcohol ingestion><chronic alcohol use><chronic ethanol consumption><chronic ethanol drinking><chronic ethanol ingestion><clustered regularly interspaced short palindromic repeats screen><congenital aplastic anemia><cultured cell line><defective nutrient sensing><deficient nutrient sensing><deregulated nutrient-sensing><deregulation of nutrient sensing><diet supplement><dietary supplements><drink heavily><drinking><dysregulated nutrient sensing><epigenetically><ethanol consumption><ethanol drinking><ethanol effect><ethanol exposed><ethanol exposure><ethanol induced injury><ethanol ingestion><ethanol intake><ethanol product use><ethanol research><ethanol sensitivity><ethanol use><ethanol-induced disorder><excessive alcohol consumption><excessive alcohol ingestion><excessive alcohol intake><excessive drinking><excessive ethanol ingestion><exposed to alcohol><exposed to ethanol><exposure to alcohol><exposure to ethanol><extreme drinking><feeding><folic acid metabolism><genetic variant><genome integrity><genomic integrity><genomic variant><germ-line defect><germline variant><heavy alcohol use><hematopoietic progenitor><hematopoietic stem cell aging><hematopoietic stem progenitor cell><hemopoietic><hemopoietic progenitor><hemopoietic stem cell><hepatic body system><hepatic disease><hepatic organ system><hepatopathy><impaired nutrient sensing><insight><liver disorder><liver transplantation><mitochondrial><model of animal><mouse model><mtDNA><murine model><myelodysplasia><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><nutritional supplement><older groups><older individuals><older person><oxidative DNA damage><pace of aging><pace of biological aging><pathway><population aging><prevent><prevent alcohol><preventing><preventing alcohol><problem drinker><progenitor cell population><progenitor population><rate of aging><rate of biological aging><repair><repair function><repaired><reparative function><response><scRNA-seq><sensitivity to alcohol><sensitivity to ethanol><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><speed of aging><speed of the aging><stem and progenitor cell population><stem cell depletion><stem cell exhaustion><stem cell fatigue><stem cell population><therapeutic target><transplant model><γH2AX>