Project Summary/Abstract: As the life expectancy of the human population continues to rise, and with the number of people aged 65 years and over projected to double over the next 30 years (16), the prevalence of age-dependent malignancies will continue to increase significantly. This is especially true for hematologic malignancies, which combined (leukemia, non-Hodgkin lymphoma, multiple myeloma) comprise amongst the most prevalent new cancer cases each year, and for which age is the most significant risk factor (17) (18). Current hypotheses suggest that this late onset of malignancy is due to alterations in hematopoietic function and output over time, thus making the study of aging hematopoiesis of critical importance to understanding and treating these diseases (19) (3) (20) (5). The aging HSC is subject to stem cell exhaustion- characterized by a decline in self-renewal, an uneven distribution of blood cell output (leading to a skew towards myeloid cell production), an accumulation of DNA damage that goes unrepaired, and an increased frequency of clonal hematopoiesis, which can lead to proliferation and production of cells that stem from an unfit parent population (21) (22) (23) (24) (25). Prostaglandin E2 (PGE2) is a multi-faceted lipid messenger involved in various physiological and pathophysiological processes, which have been shown to be especially critical for homeostatic maintenance of the hematopoietic system (6-12). We have previously characterized 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the enzyme responsible for the rate-limiting step of PGE2 degradation, as a novel therapeutic target to augment tissue regeneration in models of bone marrow (BM) transplantation (13) (14). Notably, we have demonstrated that 15-PGDH inhibition (15-PGDHi) following murine hematopoietic stem cell transplantation using aged donor and recipient mice results in accelerated multi-lineage peripheral blood recovery and an enhanced recovery of hematopoietic stem cells. These findings have further established the positive role of PGE2 and the negative role of 15-PGDH in organ self-renewal. We thus hypothesize a) that 15- PGDH is a negative regulator of age-related hematopoietic development, b) that genetic loss of 15-PGDH will result in superior organ fitness with age, and c) that PGDHi using our small molecules may be a viable therapeutic strategy to treat hematopoietic age-related malignancies. Overall, this proposal provides clear rationale to further explore the role of 15-PGDH on organ fitness with age and to explore the technique of modulating PGE2 levels in models of age-related disease.