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Principal Investigator: Michalis Agathocleous
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $346,368
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
PROJECT SUMMARY:
We have developed methods to profile the metabolome of hematopoietic stem cells (HSCs) and other rare cell
types purified from tissues. Each hematopoietic cell type had a distinct metabolite identity. Most metabolites
were enriched or depleted in specific cell types, suggesting they may have novel cell-type specific roles. HSCs
and multipotent progenitors (MPPs) in mouse and human bone marrow had high levels of ascorbate (Vitamin
C), which promoted the activity of the enzyme TET2, a suppressor of HSC function. Hematopoietic-specific
ascorbate deficiency promoted HSC function, myelopoiesis and the generation of inflammatory myeloid cells,
and caused early lethality. Ascorbate deficiency is common in the human population because in early primate
evolution we lost the ability to synthesize ascorbate. Ascorbate deficiency in healthy people is associated with
increased risk of mortality for unknown reasons. Hematopoietic TET2 loss of function mutations are also
common in humans, and drive a clonal expansion of mutant blood cells termed clonal hematopoiesis. TET2-
deficient blood cells may contribute to an increased risk of mortality. This application’s objective is to
understand the role of ascorbate in the regulation of myelopoiesis. Our central hypothesis is that ascorbate
suppresses myelopoiesis, and that ascorbate deficiency increases myelopoiesis and inflammation after
plasmodium infection. To test this hypothesis, we will use genetically engineered ascorbate deficient mice, to
mimic the human condition, and Tet2-deficient mice. In Aim 1 we will test if ascorbate suppresses the
generation of inflammatory myeloid cells by acting on HSCs or restricted myeloid progenitors, and if this is
mediated by Tet2. In Aim 2 we will determine the effects of ascorbate deficiency or Tet2 deficiency on the
myelopoietic response to Plasmodium infection in a mouse model of malaria. In Aim 3 we will investigate the
mechanisms by which ascorbate deficiency and Tet2 deficiency promote morbidity and mortality in
Plasmodium infection. These experiments may have significant public health implications. They could identify
physiological situations, such as infection, in which the presence of ascorbate deficiency and Tet2-deficient
clonal hematopoiesis are deleterious to the organism. They may also identify mechanisms by which aberrant
myelopoiesis contributes to the pathogenesis of malaria which afflicts more than 200 million people worldwide.
Terms: <Address><Ascorbic Acid><Assay><Bacteremia><Bioassay><Biological Assay><Blood Cells><Blood Plasma><Blood Precursor Cell><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><COVID-19><CV-19><Cell Body><Cell Isolation><Cell Lineage><Cell Segregation><Cell Separation><Cell Separation Technology><Cells><Clonal Expansion><Communicable Diseases><Coronavirus Infectious Disease 2019><Data><Diet><Elderly><Enzyme Gene><Enzymes><Evolution><Frequencies><Generations><Genetic Alteration><Genetic Change><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic defect><Gulo><Hematopoiesis><Hematopoietic><Hematopoietic Cellular Control Mechanisms><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Human><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Inflammatory><Inflammatory Response><L-gulono-gamma-lactone dehydrogenase><L-gulono-gamma-lactone oxidase><L-gulonolactone oxidase><L-gulonooxidase><Malaria><Measures><Mediating><Methods><Mice><Mice Mammals><Modern Man><Morbidity><Morbidity - disease rate><Multipotent Stem Cells><Murine><Mus><Mutation><Myelogenous><Myeloid><Myeloid Cells><Myeloid Progenitor><Myeloid Progenitor Cells><Myeloid Stem Cells><Myelopoiesis><Nature><Organism><Outcome><Oxidases><Paludism><Parasites><Pathogenesis><Pathogenicity><Pathology><Peripheral Blood Cell><Persons><Phenotype><Physiologic><Physiological><Plasma><Plasma Serum><Plasmodium><Plasmodium Infections><Plasmodium chabaudi><Population><Primates><Primates Mammals><Progenitor Cells><Public Health><Recombinant DNA Technology><Regulation><Reticuloendothelial System, Serum, Plasma><Rodent><Rodentia><Rodents Mammals><Role><SLC23A2 transporter><SVCT-1><SVCT1><Spleen><Spleen Reticuloendothelial System><Testing><Tissues><Transplantation><VIT C><Variant><Variation><Vertebrate Animals><Vertebrates><Vitamin C><Wolverines><Work><adult progenitor><adult stem cell><advanced age><ascorbate><ascorbic acid transporter SVCT 1><bacteraemia><bacterial sepsis><blood cell formation><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><cell sorting><cell type><cofactor><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><cytokine><death risk><diets><enzyme activity><experiment><experimental research><experimental study><experiments><genetically engineered><genome mutation><geriatric><gulonolactone><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic><hemopoietic progenitor><hemopoietic stem cell><high risk><human model><in vivo><leukemogenesis><living system><loss of function mutation><malaria infection><malaria-infected><malarial infection><metabolic profile><metabolism measurement><metabolome><metabolomics><metabonome><metabonomics><model of human><mortality><mortality risk><mouse model><multipotent progenitor><multipotent progenitor cell><murine model><mutant><myeloid stem and progenitor cell><novel><progenitor><progenitor cell function><progenitor function><response><senior citizen><social role><sodium DEPENDENDENT vitamin C transporter 1><solute carrier family 23 (nucleobase transporters), member 2><somatic progenitor><somatic stem cell><stem><stem and progenitor cell function><stem and progenitor function><stem cell function><stem cells><transplant><vertebrata>