Project 1: Targeting 15-PGDH in Colon Cancer Risk, Prevention and Treatment

项目总结/摘要 该建议的目标是开发15-PGDH和/或其在调节PGE 2的途径中的伴侣基因 降解和PGE 2合成，作为减少结直肠癌（CRC）死亡的有力生物标志物， 使个性化的策略，以改善基于风险的筛选和改善阿司匹林的化学预防。 我的团队的开创性研究表明，15-PGDH是一种结肠癌抑制剂， 介导PGE 2的降解，作为考克斯-2致癌活性的代谢抑制剂。研究中 发表在《科学》杂志上，我们还表明，15-PGDH在结肠和其他器官中起作用， 干细胞样细胞对组织损伤的增殖反应的负调节因子。此外，我们还表明， 结肠15-PGDH水平在人群中变化12倍，并且在遗传学研究中， 连锁的15-PGDH缺陷（或PGT缺陷，PGT是在PGE 2途径中与15-PGDH配对的基因 降解），增加了CRC的人类风险。我们的第一个目标是现在直接测试结肠15-PGDH作为 用于识别CRC高风险人群的生物标志物，因此需要更密集的CRC筛查，然后 测试我们的假设，即与15-PGDH合作介导的6个基因表达的综合分析， PGE 2降解和合成（即推断的PGE 2的基因签名）将是一个更强的预测因子。 CRC高危人群。此外，在发表在《科学转化医学》上的具有里程碑意义的研究中，我们 已经表明，15-PGDH也是使用阿司匹林预防CRC的个体的决定性因素， 仅在结肠15-PGDH高的个体中有效降低CRC风险，在个体中无效 具有低结肠15-PGDH水平的患者（即有效的CRC预防需要降低 考克斯抑制剂（阿司匹林）的PGE 2与高结肠15-PGDH一起作用）。我们的第二个目标是现在提供 改变结肠15-PGDH作为阿司匹林敏感性与耐药性生物标志物的临床复制的实践 在一个新的，更大的，人类验证人群中进行化学预防，并进一步验证我们的假设，即6- 推断的PGE 2基因特征将是识别将受益的个体的更强预测因子 使用阿司匹林来降低CRC风险。最后，在《临床研究杂志》上发表的研究中， 显示炎症途径有效抑制结肠15-PGDH表达。我们的第三个目标现在测试 假设i）与CRC风险和炎性紧张度相关的生活方式因素（例如肥胖、缺乏 运动和饮食红肉）通过调节15-PGDH及其推断的PGE 2的6个伴侣基因起作用 特征;以及ii）改变这些生活方式因素可以将推断的PGE 2的特征向特征转移 预示着阿司匹林更敏感。我们通过i）检验生活方式与 人结肠表达15-PGDH和推断的PGE 2的特征的因子，和ii）在人结肠表达15-PGDH中的功能测试。 iia）改变基因表达（推断的PGE 2），iib）改变结肠PGE 2，和 iic）增强NSAID降低结肠PGE 2活性。

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to develop 15-PGDH, and/or its partner genes in the pathways that regulate PGE2 degradation and PGE2 synthesis, as a powerful biomarker for reducing deaths from colorectal cancer (CRC), by enabling personalized strategies to improve risk-based screening and to improve aspirin chemoprevention. Groundbreaking studies from my group have shown that 15-PGDH is a colon cancer suppressor that, by mediating degradation of PGE2, acts as a metabolic suppressor of the oncogenic activity of COX-2. In studies published in Science, we have moreover shown that 15-PGDH acts in the colon, and in other organs, as a negative regulator of the proliferative response of stem like cells to tissue injury. We furthermore have shown that colon 15-PGDH levels vary by 12-fold over the human population, and, in genetics studies, have indirectly linked 15-PGDH deficiency (or deficiency of PGT, a gene that partners with 15-PGDH in the pathway of PGE2 degradation) with increased human risk of CRC. Our first aim is to now directly test colon 15-PGDH as a biomarker for recognizing humans at high CRC risk, who thus need more intensive CRC screening, and to then test our hypothesis that an integrated analysis of expression of the 6 genes that partner with 15-PGDH to mediate PGE2 degradation and synthesis (i.e. a genetic signature of inferred PGE2) will be an even stronger predictor of individuals at high CRC risk. Moreover, in landmark studies, published in Science Translational Medicine, we have shown that 15-PGDH is also determinative of individuals in whom using aspirin prevents CRC, with aspirin only effective in lowering CRC risk in individuals who have high colon 15-PGDH, and ineffective in individuals who have low colon 15-PGDH levels (i.e. effective CRC prevention requires the synergistic activity in lowering PGE2 of a COX inhibitor (aspirin) acting together with high colon 15-PGDH). Our second aim is to now provide a practice changing clinical replication of colon 15-PGDH as a biomarker of sensitivity versus resistance to aspirin chemoprevention in a new, larger, human validation population, and further, to test our hypothesis that the 6- gene signature of inferred PGE2 will be an even stronger predictor for recognizing individuals who will benefit from using aspirin to reduce CRC risk. Last, in studies published the Journal of Clinical Investigation, we have shown that inflammatory pathways potently suppress colon 15-PGDH expression. Our third aim now tests the hypotheses that i) lifestyle factors that are linked to both CRC risk and to inflammatory tone (e.g. obesity, lack of exercise, and dietary red meat) act by regulating 15-PGDH and its 6 partner genes of the inferred PGE2 signature; and ii) that modifying these lifestyle factors can shift the signature of inferred PGE2 toward a profile predictive of greater aspirin sensitivity. We interrogate this hypothesis by i) testing for association of lifestyle factors to human colon expression of 15-PGDH and the signature of inferred PGE2, and ii) functional testing in mouse models for these factors ability to: iia) alter gene expression (inferred PGE2), iib) alter colon PGE2, and iic) potentiate NSAID's activity in lowering colon PGE2.