Targeting 15-PGDH in Age-Related Hematologic Disease

项目摘要/摘要： 随着人类预期寿命的不断提高，以及65岁以上人口的数量 预计未来30年(16)，与年龄相关的恶性肿瘤的患病率将翻一番。 继续大幅增加。对于恶性血液病来说尤其如此，它们结合在一起 (白血病、非霍奇金淋巴瘤、多发性骨髓瘤)是最常见的新癌症 其中，年龄是最重要的风险因素(17)(18)。目前的假说表明 这种较晚的恶性发作是由于随着时间的推移，造血功能和输出量的改变，因此 对衰老造血的研究对认识和治疗这些疾病具有重要意义 (19)(3)(20)(5)。老化的HSC容易受到干细胞耗尽的影响--其特征是自我更新能力下降。 血细胞产量分布不均(导致向髓系细胞生产倾斜)， 无法修复的DNA损伤的积累，克隆造血频率的增加， 这可能导致来自不适合的亲本群体的细胞的增殖和生产(21)(22)(23) (24)(25)。前列腺素E2(PGE2)是一种多方面的脂质信使，参与多种生理和病理过程。 病理生理过程，已被证明是特别关键的动态平衡维持 造血系统(6-12)。我们之前已经鉴定了15-羟基前列腺素脱氢酶 作为一种新的治疗方法，负责PGE2降解限速步骤的酶(15-PGDH) 目的增强骨髓移植模型中的组织再生(13)(14)。值得注意的是，我们 已证实15-前列腺素脱氢酶(15-PGDH)对小鼠造血干细胞的抑制作用 使用老年供受者小鼠进行移植可加速多血统的外周血细胞 恢复和加强造血干细胞的恢复。这些发现进一步证实了 前列腺素E_2在器官自我更新中的积极作用和15-前列腺素脱氢酶的负性作用。因此，我们假设a)15- 前列腺素脱氢酶是与年龄相关的造血发育的负调节因子，b)15-前列腺素脱氢酶基因缺失将 C)使用我们的小分子的PGDHi可能是一种可行的 治疗血液系统年龄相关恶性肿瘤的治疗策略。总体而言，这项提案提供了明确的 进一步探讨15-前列腺素脱氢酶对器官适龄的作用及其技术基础 在年龄相关疾病模型中调节前列腺素E_2水平。

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.