Effects of inflammaging on intestinal epithelial cells and aspirin chemoprevention.

炎症对肠上皮细胞的影响和阿司匹林化学预防。

• 批准号: 10383683
• 负责人: Andrew T Chan
• 金额: $ 60.03万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-05 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10383683
• 关键词: APC gene; Address; Adult; Advisory Committees; Age; Aging; Aspirin; Benefits and Risks; Biological; Biological Assay; Biological Markers; Biopsy; Cancer Model; Cell Count; Cell Culture Techniques; Cell physiology; Cells; Chemoprevention; Chemopreventive Agent; Chemoprotective Agent; Chronic Disease; Clinical; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal Cancer; Data; Depreciation; Development; Dinoprostone; Dose; Double-Blind Method; Elderly; Enrollment; Epithelial; Epithelial Cells; Etiology; Experimental Models; Gene Expression Profile; Genetic; Guidelines; Human; Incidence; Individual; Inflammaging; Inflammatory; Intervention; Intestinal Cancer; Intestines; LGR5 gene; Lead; Life; Measures; Mediating; Methods; Modeling; Mucous Membrane; Mus; Mutation; Non-Steroidal Anti-Inflammatory Agents; Oncogenic; Organoids; Pathway interactions; Patients; Pharmacology; Placebo Control; Population; Pre-Clinical Model; Preventive service; Process; Prostaglandin Inhibition; Prostaglandins; Randomized Controlled Trials; Reporter; Reporting; Resistance; Resolution; Role; Secondary to; Shapes; Signal Transduction; Small Intestines; Testing; age effect; age related; aged; anti-cancer; biomarker development; cancer biomarkers; colorectal cancer prevention; colorectal cancer risk; disorder prevention; epithelial stem cell; fetal; human old age (65+); in vitro Model; in vivo; intestinal epithelium; mortality; mouse model; novel; pre-clinical; premalignant; receptor; regenerative; single-cell RNA sequencing; stem cell function; stem cells; tumor; tumor initiation; tumor progression; tumorigenesis; tumorigenic; urinary; young adult

PROJECT ABSTRACT Previous randomized controlled trials (RCT)s demonstrate that low-dose aspirin (LDA, 81-100mg/day) reduces the risk of colorectal cancer (CRC). The U.S. Preventive Services Task Force (USPSTF) recommends LDA to prevent CRC in adults aged 50-59. However, a recent RCT among 19,114 older (65+) individuals reported that initiating LDA late in life had no benefit on CRC incidence and was potentially detrimental for mortality. Because CRC incidence rises with age, understanding the relationship and functional impact of aging on the chemopreventive effects of LDA is a high priority. Our working model is that the effect of LDA on the colon differs in older individuals due to age-related changes in intestinal stem cell (ISC) number and function secondary to a process of higher basal inflammatory tone, a.k.a. “inflammaging”. Normally, CRC appears to be primarily driven by oncogenic mutations in Lgr5+ ISCs and aspirin-like NSAIDs appear to preferentially eliminate premalignant Lgr5+ ISCs. However, our preliminary data demonstrates that old mice (20-22 months [mos]), as compared to young mice (2-3 mos), have fewer, less regenerative small intestinal Lgr5+ ISCs, which are also less tumorigenic in an Apc tumor suppressor model. Nonetheless, like humans, aged mice spontaneously develop a greater number of tumors, indicating that non-Lgr5+ cells are also the origin of intestinal cancers in aged mice and that these cells are less sensitive to LDA. LDA modulates prostaglandin (PG) levels, including PGE2. We also find that PGE2 impacts ISC function through its receptor Ptger4 and this signaling can drive ISCs into a fetal-like state (Hopx+) that is mediated by Hippo/Yap signaling. Thus, in the setting of inflammaging, elevated PGE2 may irreversibly compromise the colon (cISC) pool leading to compensatory functions within select cISCs that promote tumorigenesis. Through our double-blind, placebo-controlled RCT, we demonstrated that modulation of PG tone and inhibition of PG synthesis is central to aspirin’s mode of action. Our central hypothesis is that aging and age-related processes promote a decrease in the cISC pool (Lgr5+ cISCs) that is normally sensitive to aspirin chemoprevention. We propose that initiation of LDA earlier in life protects against this age-related, inflammation-associated, and/or PGE2-mediated damage to the cISC pool. In contrast, with advancing age there may be a “point-of-no-return” in which initiation of LDA is no longer protective against age- related changes in the cISC pool. In this proposal, we will expand our existing RCT to examine the impact of LDA on colonic epithelium at single cell resolution, patient-derived organoids, and urinary PGs in older adults. We will use novel in vivo preclinical models to dissect the role of inflammaging on PG signaling and LDA on cISCs. We will then examine the causality of these pathways on colon tumor incidence and progression. These studies may offer a biological explanation for the unexpected finding of a differential effect of LDA in older adults, which may influence clinical guidelines or the development of biomarkers to optimize LDA’s risk-benefit profile.

项目摘要 先前的随机对照试验 (RCT) 表明，低剂量阿司匹林（LDA，81-100 毫克/天）可降低 结直肠癌 (CRC) 的风险。美国预防服务工作组 (USPSTF) 建议 LDA 预防 50-59 岁成年人的 CRC。然而，最近一项针对 19,114 名老年人（65 岁以上）的随机对照试验报告称 晚年开始 LDA 对 CRC 发病率没有任何益处，并且可能不利于死亡率。因为 结直肠癌的发病率随着年龄的增长而上升，了解衰老对结直肠癌的关系和功能影响 LDA 的化学预防作用是重中之重。我们的工作模型是 LDA 对结肠的影响 由于肠干细胞（ISC）数量和功能与年龄相关的变化，老年人的情况有所不同 到较高基础炎症张力的过程，又名“炎症”。通常情况下，CRC 似乎主要是 由 Lgr5+ ISC 和阿司匹林样 NSAID 的致癌突变驱动的药物似乎优先消除 癌前 Lgr5+ ISC。然而，我们的初步数据表明，老年小鼠（20-22 个月 [mos]）， 与年轻小鼠（2-3 个月）相比，其小肠 Lgr5+ ISC 数量较少且再生能力较差， 在 Apc 肿瘤抑制模型中致瘤性较低。尽管如此，和人类一样，老鼠也会自发衰老 产生更多的肿瘤，表明非 Lgr5+ 细胞也是肠癌的起源 老年小鼠，这些细胞对 LDA 不太敏感。 LDA 调节前列腺素 (PG) 水平，包括 前列腺素E2。我们还发现 PGE2 通过其受体 Ptger4 影响 ISC 功能，并且该信号传导可以驱动 ISC 进入由 Hippo/Yap 信号传导介导的胎儿样状态 (Hopx+)。因此，在炎症的情况下， PGE2 升高可能会不可逆地损害结肠 (cISC) 池，导致结肠内的代偿功能 选择促进肿瘤发生的cISC。通过我们的双盲、安慰剂对照随机对照试验，我们证明了 调节 PG 张力和抑制 PG 合成是阿司匹林作用方式的核心。我们的中央 假设是衰老和与年龄相关的过程会促进 cISC 库（Lgr5+ cISC）的减少，即 通常对阿司匹林化学预防敏感。我们建议在生命早期开始 LDA 可以防止 这种与年龄相关、炎症相关和/或 PGE2 介导的 cISC 池损伤。相比之下，与 随着年龄的增长，可能会出现一个“不归路”，即 LDA 的启动不再能够预防年龄增长。 cISC 池中的相关更改。在本提案中，我们将扩展现有的随机对照试验（RCT）来研究以下问题的影响： 单细胞分辨率的结肠上皮、患者来源的类器官和老年人尿液 PG 的 LDA。 我们将使用新颖的体内临床前模型来剖析炎症对 PG 信号传导和 LDA 的作用 cISC。然后我们将检查这些途径与结肠肿瘤发生和进展的因果关系。这些 研究可能为 LDA 对老年人的差异效应这一意外发现提供生物学解释， 这可能会影响临床指南或生物标志物的开发，以优化 LDA 的风险收益状况。