Targeting 15-PGDH in Age-Related Hematologic Disease

靶向 15-PGDH 治疗年龄相关性血液疾病

• 批准号: 10582765
• 负责人: Amar Desai
• 金额: $ 20.13万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10582765
• 关键词: Acceleration; Age; Aging; Anemia; Animals; Aplastic Anemia; Biological Assay; Blood Cells; Bone Marrow; Bone Marrow Transplantation; Cell Cycle; Characteristics; Complete Blood Count; DNA Damage; Development; Dinoprostone; Disease; Dose; Dysmyelopoietic Syndromes; Engraftment; Enzymes; Erythroid; Frequencies; Genetic; Hematologic Neoplasms; Hematological Disease; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic System; Hematopoietic stem cells; Heterozygote; Homeostasis; Homing; Human; Immune System Diseases; Inflammatory; Knock-out; Knockout Mice; Leukocytosis; Life Expectancy; Lipids; Lymphoid; Maintenance; Malignant Neoplasms; Measures; Mediating; Megakaryocytes; Modeling; Molecular; Multiple Myeloma; Mus; Myelofibrosis; Myelogenous; Myeloid Cells; Myeloproliferative disease; Natural regeneration; Non-Hodgkin' s Lymphoma; Onset of illness; Organ; Output; Oxidoreductase; Parents; Pathogenesis; Persons; Phenocopy; Phenotype; Physiological; Population; Prevalence; Process; Production; Proliferating; Public Health; Pulmonary Fibrosis; Recovery; Regenerative capacity; Research; Risk Factors; Role; S-Phase Fraction; Signal Pathway; Signal Transduction; Spleen; Techniques; Testing; Therapeutic; Time; Tissues; Transplantation; Treatment Efficacy; Wild Type Mouse; Work; age related; aged; aging population; exhaustion; fitness; genetic signature; hematopoietic stem cell aging; hematopoietic stem cell self-renewal; inhibitor; knockout animal; leukemia; mouse model; mutant; new therapeutic target; novel; peripheral blood; pharmacologic; prevent; protein expression; regenerative; regenerative tissue; self-renewal; small molecule; stem; stem cell function; stem cell niche; stem cells; thrombocytosis; tissue regeneration; tissue stem cells; transcriptome sequencing

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.

项目概要/摘要： 随着人口预期寿命的持续增长，65岁以上的人口数量不断增加， 预计在未来30年内将翻一番（16），年龄依赖性恶性肿瘤的患病率将 继续大幅增加。对于血液恶性肿瘤尤其如此， （白血病、非霍奇金淋巴瘤、多发性骨髓瘤）包括最普遍的新癌症 病例每年，其中年龄是最重要的风险因素（17）（18）。目前的假设表明 这种恶性肿瘤的迟发是由于造血功能和输出随时间的改变，因此， 使衰老造血的研究对理解和治疗这些疾病至关重要 (19)（3）（20）（5）.衰老的HSC会受到干细胞耗竭的影响-其特征是自我更新能力下降， 血细胞输出的不均匀分布（导致向骨髓细胞生产倾斜）， 未修复的DNA损伤的积累，以及克隆造血的频率增加， 其可导致源自不合适的亲本群体的细胞的增殖和产生（21）（22）（23） (24)（25）.前列腺素E2（PGE 2）是一种多功能的脂质信使，参与多种生理和 病理生理过程，这已被证明是特别重要的稳态维持 造血系统（6-12）。我们以前已经确定了15-羟基前列腺素脱氢酶 （15-PGDH），负责PGE 2降解的限速步骤的酶，作为一种新的治疗剂 靶向增强骨髓（BM）移植模型中组织再生（13）（14）。值得注意的是， 已经证明，在小鼠造血干细胞移植后，15-PGDH抑制（15-PGDHi） 使用老年供体和受体小鼠的移植导致加速的多谱系外周血 造血干细胞的恢复和增强的恢复。这些发现进一步确立了 PGE 2的积极作用和15-PGDH的消极作用在器官自我更新。因此，我们假设a）15- PGDH是与年龄相关的造血发育的负调节剂，B）15-PGDH的遗传丢失将 导致上级器官适应性随着年龄的增长，和c）PGDHi使用我们的小分子可能是一个可行的 治疗造血年龄相关恶性肿瘤的治疗策略。总的来说，该提案提供了明确的 进一步探索15-PGDH对随年龄增长的器官适应性的作用以及探索 在年龄相关疾病模型中调节PGE 2水平。